Sick Sinus Syndrome

AKA sinus node dysfunction.

• Commonest cause is ageing associated dysfunction of the SA node and and surrounding atrial myocardium. Other are infiltration, surgery etc. Primarily affects elderly people.
• Patients with SND are typically symptomatic with fatigue, lightheadedness, palpitations, presyncope, and/or syncope
• Electrolyte abnormalities, hypoxia and hypothermia can cause sinus dysfunction. Hypoxia during OSA can also cause SND.
• Symptoms:
• Alternating bradycardia and atrial tachyarrhythmias in over 50 percent of cases
• Sinus pauses, arrest, and sinoatrial (SA) exit block with
• Alternating bradycardia and atrial tachyarrhythmias in over 50 percent of cases [1,4-9]. Atrial fibrillation is most common, but atrial flutter and paroxysmal supraventricular tachycardias (ie, due to atrial tachycardia) may also occur.
  • The transient resolution of AF in tachybrady syndrome leads to prolonged sinus pause which can cause syncope.
• Management
  • Acute
    • Haemodynamically unstable: this is rare; But if present -> temporary pacing, adrenaline, atropine, dopamine.
    • If stable, monitor until definitive therapy.
  • Long term:
    • If asymptomatic, monitor regularly.
    • If symptomatic, implantable pacemaker.

    - aminophylline is a complex of (theophylline and ethylenediamine) 

Source

Pneumoconioses

• causes by deposition of particles which elicit and inflammatory response.

Asbestosis	Silicosis	Berylliosis
Primary from mining; Secondary exposure from using in manufacturing	Sand blasting etc	Electronics manufacture
Fibrous form of Magneiusm Silicate	SiO2 crystals	?Beryllium
Two Forms: Chrysolite - white asbestos, serpentien fibers - less harmful. Crosydolite - blue asbestos, straight fibers, more harmful
Pleural plaques 20 to 30 years after exposure - most on rib associated surfaace of pleura Benign effusions Diffuse pleural thickening Mesotheliomas Bronchial Carcinomas
	SiO2 crystals persist cause necrosis of phagocytosing macrophages -> enzymes release -> lung damage. (cessation of exoposure doens't hald lung damage); Macrophage toxicity predisposes to post primary tuberculosis.
Lower lobe predilection	Upper lobe fibrosis with lymph nodes which can calcify	Upper lobe predilection.

Causes of dominant R wave in V1

#2016GM-APR/Q01
RVH, Right sided Heart, RBB, Posterior MI

• Normal in children and young adults
• Right Ventricular Hypertrophy (RVH)
  • Pulmonary Embolus
  • Persistence of infantile pattern
  • Left to right shunt
• Right Bundle Branch Block (RBBB)
• Posterior Myocardial Infarction (ST elevation in Leads V7, V8, V9)
• Wolff-Parkinson-White (WPW) Type A
• Incorrect lead placement (e.g. V1 and V3 reversed)
• Dextrocardia (right sided heart)
• Hypertrophic cardiomyopathy
• Dystrophy
  • Myotonic dystrophy
  • Duchenne Muscular dystrophy
    -Source

[!INFO] Summary

LBBB	RBBB
Always pathological	Can be benign
Causes LAD	No effect on axis
Affects MI diagnosis	No effect on MI diagnosis

• New onset LBBB is always pathological, never ignore!
  • Sgarbossa criteria are used in this case.
  • Mnemonic: Hypertrophy or dilation of LV can cause LBBB.
• Idiopathic fibrosis, digoxin toxicity, hyperkalemia
• Cardiac scarring - disrupts conduction system
• Cardiac infiltration - disrupts conduction system. (amyloidosis)
  • RBBB is frequently asymptomatic and in this case, there is no risk of adverse outcomes.
  • Acute cor pulmonae (pulmonary embolism) can also cause RBBB.

[!TIP] Mnemonic: It seems that increase in ventricular afterload can cause ipsilateral bundle branch blocks.
? cause of LAD in LBBB?
?is it because The counterbalancing effect of RV depolarization on the axis is lost as the RV depolarizes later??
Verapamil is a suitable alternative for adenosine if it it contraindicated.

[!INFO] AV nodal blocking drugs
Source: Harrison's
Mnemonic: AV nodal Blocking drugs : AVB -> Adenosine, verapamil, beta blockers (after trying vagal maneuvers)
(+? others)

[!INFO] Mnemonics:
Adenocarcinoma : Acchis
SQCs : Smokers
4. Diagnosis: By anti-P/Q-type voltage-gated calcium channel (VGCC) antibody testing and high frequency RNS (repetitive nerves stimulation)
5. Targeted therapy for symptomatic LEMS with 3,4-diaminopyridine is usually first line.
6. Refractory cases : immunosuppressants and plasma exchange.

• Tendency to fall increases osteoporosis risk
• Obesity reduces osteoporosis
• Thiazide diuretics raises calcium so it helps bone density.
• Hypophosphataemia causes osteoporosis
• Teriparatide (although it is a form of PTH) reduces osteoporosis. (activates more osteoblasts than osteoclasts)

[!TIP] Hypercalcemia: Abdominal groans, psychich moans and renal stones.

Comparison of ABPA, EGPA and Hypersensitivity pneumonitis

Allergic bronchopulmonary aspergillosis
[[passMedicine Summaries#Hypersensitivity pneumonitis (HP)|Hypersensitivity Pneumonitis]]

• 3 times more common in women
• most commonly diagnosed in people aged 20-40 years
  • Relapses are caused by acute inflammation causing myelin damage and conduction block.
• Demyelination has a prediliction of cervical spinal cord, optic nerves, corpus callosum, cerebellar connections of the brainstem. (contrast with [[HIV-AIDS#^13ac5c|PML]] where spinal cord and optic nerves are spared)
  • PML can be cause by reactivation of JC virus which in turn can be promoted by therapy with natalizumab!!. (which is used to treat MS)

• Cerebellar: charcot triad -> Scanning speech (i.e dysarthria), nystagmus and intention tremmor. Youtube (mnemonic: No taxes for disabled)
• Uhthoff phenomenon - symptoms worsen in high temperatures.
• Lhermitte's sign - Electrical shock sensation running down the back when neck is flexed.
  • Fingolimod - sphingosine receptor modulator
    paracetamol overdose.

Complications of ileal resection

• B12 malabsorption
• Bile salt malabsorption
  • causing diarrhoea due to colonic irritation
  • Depletion of bile salts -> Steatorrhoea
• Folate and iron deficiency are possible.
• Increased incidence of cholelithiasis and urolithiasis.
• Source

| Metformin | Biguanide | Insulin sensitiztion Reduce hepatic gluconeogenesis.It activates AMPK (AMP activated protein kinase) | GI side effects Lactic acidosis (risk in renal/liver/heart failure – contrindications) No weight gain May reduce apetite, STOP when eGFR < 30 | Reduced GI B12 absorption The usual first line agent, can be combined with other | Lower FBS by about 50 mg/dL Lowers HbA1C by about 1% |
Mechanism of action: Increases intracellular c-AMP potentiated insulin secretion.

• Malignancies

• "Antiphospholipid antibodies" is a collective term for several of antibodies including anti cardiolipin antibodies and lupus anticoagulant and anti-beta2 glycoprotein I.

After initial detection on the FBC, the investigation of choice is immunophenotyping by flow cytometry to reveal cell surface markers typical of CLL, including CD5, CD19 and CD20.

Background physiology of lymphocytes

Source-YouTube
Source-YouTube
Source-YouTube

• Different B cells are sensitive to different antigens.

• Binding of the pathogen to B cell receptors (which are membrane bound antibodies) causes B cell activation.

• But Activation of B cells also requires co-stimulation by (activated) TH cells. The B cell engulfs the pathogen via receptor mediated endocytosis and presents antigen on an MHC II molecule. A Th cell reactive to this antigen will arrive, bind and activate the B cell. (this makes B cells professional APCs)
  • To complicate things, b cells require two signals from the Th cell to become activated. There is also a less potent form of b cell activation - T cell independent activation which is dependent on B cell receptor crosslinking by antigents - but this method is less potent.
  • 
• After activation, B cells become effector cells or memory cells.
  • Effector cells renter the cell cycle and begin to proliferate and produces antibodies -> The antibody producing cells are called plasma cells
  • memory cells persist for memory.
• T cell also require activation and after activation they become effector and memory T cells.
• Th cells have CD4 receptors which bind to MHC Class II and get activated by APCs.
• Tc cells have CD8 receptors which bind to MCH Class I and get activated by 'all nucleated cells' which present an antigen.
• See [[2021 Basic Sciences July#HLA molecules|HLA Molecules]]
• After activation,
  • Effector Th cells -> activate B lymphocytes and secrete cytokines. ("alarm ringer") (one such cytokine is interferron gamma)
  • Effector Tc cells kill host cells.
  • Memory cells of both types persist.
• B cells can undergo activation and class switching.
  • T cell activation of B cells occurs in the lymph nodes.
  • naive B cells have membrane bound IgM and IgD.
  • First step after activation is somatic hypermutation. This generates B cells with various affinities for the same specific antigen. Low affinity B cells die and high affinity B cells survive.
  • The surviving high affinity B cells will undergo class witching.
  • once activated, they will produced IgG / M/ D etc. (rather than their naive state IgM). This is called isotype switching or class switching
  • Isotype switching is irreversible. It is done by altering DNA coding for the Fc region of antibodies.
  • Once class switching is done, the cell is called a plasma cell.
  • The type of antibody produced as a result of class witching depends on which cytokine was secreted by the activating T cell.
    • IL4 -> promotes IgG or IgE
    • TGF-beta -> IgG2b, IgA
    • IL5 -> IgA
    • IFN-gamma -> IgG2a or IgG3
  • Hyper IgM Syndrome: CD40 ligand signalling is defective; these individuals cannot class switch; they can only generate IgM. Individuals are immunocompromised.

Natural killer cells

• Are CD8+ T cells which do not have a TCR (T Cell receptor).
• They have receptors for MHC molecules. Stimulation of these receptors results in inhibition of killing.
• NK cells will kill any host cell that doesn't express MHC molecules.
• So any (host) cell that does not express adequate MHC molecules cannot inhibit NK cells and is killed by NK cells.
• 
• Source
• 
• Source

Chronic lymphocytic leukemia features

• Chronic lymphocytic leukemias are characterized by accumulation of mature B or T lymphocytes in the blood.
• This is manifested as chronic persistent lymphocytosis.
• Distinction between non-Hodgkin lymphoma and chronic leukemia is not rigid and depends on the proportion of disease present in soft tissue Vs. Blood.

GVHD can occur after allogenic haemotopoietic cell transplantation or with solid organs containing lymphoid tissue. (Bowel transplant was one example)
GVHD arises when immune cells transplanted from a non-identical donor graft into the recipient (host), recognize the host cells as "foreign," thereby initiating a graft-versus-host reaction.

    - **Dermatitis** - painful, pruritic rash.  (not vessicles like in the mnemonic) 
- ![RashOfGraftVsHostDisease.png](RashOfGraftVsHostDisease.png)

14. Progressive multifocal leukoencephalopathy (PML) ^13ac5c

#2016GM-OCT/Q29

• Pincu - few weeks to several months.
• Leishmaniasis causes suppurative granulomas
• Protozoan parasite.
  In SL, leishmaniasis is reported mainly in Anuradphapura, polonnaruwa, hambantota and Matara. The disease was began spreading locally in the 1990s. Incidence has been increasing rapidly in the past decade.
• In Sri Lanka, Leishmania donovani (usually associated with visceral leshmaniasis (VL)) causes cutaneous leishmaniasis (CL). This is termed dermotropism. However, it can cause VL as well.
• Phelbotomus argentipes is the main vector in SL although others are also present.
• In SL, Leishmania incidence is seasonal.

Leishmaniasis: spectrum of disease.

Leishmaniasis has a wide spectrum of disease

At one end of the spectrum, mucosal leishmaniasis (ML) and leishmaniasis recidivans (LR) are caused by oligoparasitic disease associated with a marked cellular immune response.
The center of the spectrum consists of localized cutaneous leishmaniasis (LCL), which is the most common clinical presentation.
At the opposite end of the spectrum, diffuse cutaneous leishmaniasis (DCL) is caused by polyparasitic disease with a predominance of parasitized macrophages and no granulomatous inflammation.

Cutaneous leishmaniasis

This is the commoner form in Sri Lanka.
Symptoms:

• lesions are NOT painful.
• Regional lymphadenopathy may be present.
• Satellite nodules can be present.
  Diagnosis:
• Suspect in a patient with chronic skin lesions! (i.e not in the acute stage)
• Diagnosis is by demonstration of the parasite in a clinical specimen (usually skin) by histology, culture, or molecular analysis via polymerase chain reaction (PCR)

Diffuse cutaneous

Musocal leishmaniasis

Visceral leishmaniasis

• "black fever" refers to the grayish skin colouration that develop probably due to cytokine dysregulation.

• Main reservoir in Asia is dogs and foxes. (mnemonic: Dogs itch)

  • 

• #hepatosplenomegaly with #lymphadenopathy (but lymphadenopathy isn't common)

• Commonest presentation is with abrupt onset fever with chills and rigors which then continues for weeks.

• Splenomegaly seen by second week followed by hepatomegaly.

• Lymphadenopathy is seem but is rare in the indian subcontinent.

• weight loss

• Pancytopaenia can lead to thrombocytopenia which causes epistaxis, petechiae, purpura or other bleeding.

• Complications: DIC or macrophage activation syndrome.

• Diagnosis: Identification of the organisms in aspirate of bone marrow or liver or spleen.

  • sensitivities: spleen (90%) -> Bone marrow -> lymph nodes.
  • Biopsy shows typical kineoplast in the parasite.
  • Also montenigro test (similar to mantoux test for TB) - but this test is negative in the active phase of the disease. It also remains positive for life so in endemic areas, 70% are positive.

• Other investigations:

  • pancytopaenia, hypoalbuminaemia, and hypergammaglobulinaemia.

• Treatment: pentavalent antimony salts (Sodium stibogluconate / melumine antimoniate) OR IV liposomal amphotericin B and IM paromomycin. Some patients develop post kalar-azar dermal leishmaniasis.

Post-kala-azar dermal leishmaniasis (PKDL) is a complication of visceral leishmaniasis (VL); it is characterised by a macular, maculopapular, and nodular rash in a patient who has recovered from VL and who is otherwise well.

• Mimics leprosy in appearance but there is no sensory loss.
• Perioral region is the earliest affected.
• Lymphadenopathy may be observed in East African VL but is rare outside this region.

• Based on this chart: primary FSGS seems more likely to cause nephrotic syndrome and secondary FSGS appears to be more likely to cause proteinuria.

2. Hypercoaulable states can occur, specially with membranous nephropathy.
3. Sepsis is a major cause of death due to loss of immunoglobulin -> pneumococcal infections
4. Lipid abnormalities -> increased cardiovascular risk.
5. ACEi / ARB are indicated for all patients with nephrotic range proteinuria.

• mnemonic: DAS-clones
  

4. ?monoclonal deposition disease (presents with nephrotic range proteinuria

• Majority are idiopathic.
• Infections like syphilis, TB, mycoplasma.

[!INFO] What "Effacement" means:
"Errasing, dissapearance". (like effacement of the cervix)

In this phenomenon, the normal interdigitated foot processes are finally reorganized into a broad flattened process like a paddle. The morphological process of the foot process effacement has not fully elucidated. Source

FSGS

• FSGS - Focal areas of mesangial collapse and sclerosis.
• Causes: Idiopathic, HIV infection, previous glomerular disease, massive obesity.
• In FSGS, disctintion between primary and secondary FSGS is important as treatment differs
• Clinical picture is ==more towards nephritic== in secondary FSGS.
• FSGS recurs in transplanted kidneys.
• Corresponding with the focal nature of the sclerosis, most of the affected glomeruli are at the level of the corticomedullary junction; so superficial biopsies can miss the affected glomeruli .
• 

FSGS is more likely with inflammatory conditions like SLE - PasTest

FSGS pathology:

Source

in embryonic mice, parietal epithelial cells can migrate to the visceral layer and replace damaged podocytes (Right) but in the older mice, such replacement can't occur and results in sclerosis. (left)

Source

Minimal change Vs. FSGS

[!TIP]
MCD and FSGS are like cousins; FSGS is the evil cousin.

• Haematuria is commoner in FSGS than in MCD.
• MCD shows selective protein loss -> i.e mainly albumin and not higher molecular weight proteins like immunoglobulins. FSGS shows non-selective proteinuria.
• FSGS shows poor response to corticosteroids.
• Higher percentage of FSGS patients go on to develop CKD (50%). (adults have worse prognosis)
• MCD and FSGS both show minimal / no immune deposits.
• FSGS : FSGS changes are visible on light microscopy. MCD: few changes visible on light microscopy.

c | Electron microscopy image showing subepithelial electron-dense deposits (spikes)(black arrows) and basement membrane material between the electron-dense deposits (white arrows; 4,800×).

• Subepithelial deposits, granular IgG deposition. Immunofluorescence patter: granular.
  • mnemonic: All the metals; silver stains can be used to delineate the histolgy of membranous nephropathy.
• About 1/3 have spontaneous remission. 40% go on to have CKD; proteinuria is often persistent even if there's no CKD.
• Non selective protein loss; (albumin + other proteins)
• Type 1: subendothelial immune complex deposition -> splitting of capillary basement membrane -> tramline appearance. (Mnemonic: "All aboard the proliferative train") -> Tramlines

• Myasthenia gravis is associated with thymomas. 40% of patients with Thymoma have MG.
• Thymoma is the commonest tumour of the anterior mediastinum and is diagnosed in the 50s and 60s. Thymomas can cause airway compression (SOB) and cardiac tamponade.
• 
  | Myasthenia gravis | Lambert eaton symdrome |
  | --------------------------------------- | ------------------------------------------------------------- |
  | anti AchR antibofy | Antibody against voltage gated calcium channel |
  | | [[Hypertension in pregnancy#^cd77f6|Lambert Eaton syndrome]] |
  | | |
  | Facial and eye muscles and 'moves down' | predominant proximal muscle weakness (esp. of hip girlde) |
  | | 1st line Rx: 3,4-diaminopyridine |
  | | Cranial nerve involvement less than in MG |

[!INFO] Stroke guidelines
[[NG-Management-of-Stroke-Book.pdf]]

Acute management of TIA

And along with the above, high intensity statin should be commenced immediately.

Secondary prevention of stroke:

• For TIA
  • Low Risk TIA : Aspirin alone
  • High risk TIA: DAPT (Aspirin + clopidogrel)
• For minor stroke:
  • DAPT (aspirin + clopidogrel)
• For Major stroke - Single antiplatelet therapy.
  • Aspirin alone (75-300) daily / clopidogrel alone (75) daily / Aspirin + dipyridamole bd 75+ Extended release 200)

Common problems in geriatric medicine are

• Frailty - #2021GM-JUL/Q02, #2016GM-OCT/Q
• Sarcopenia: progressive, systemic muscle disorder which leads to loss of muscle fibers, in particular fast twitch fibers.

Falls

#2016GM-OCT/Q25
#2016GM-APR/Q06

• Polypharmacy is also a risk factor for falls.
• NSAID use is also a risk for falls.

Right ventricular infarction

• Suspect and look for right ventricular infarction in all patients with inferior STEMI
  Suspect when:

• ST elevation in V1

• ST elevation in V1 and ST depression in V2 (highly specific for RV infarction)

• Isoelectric ST segment in V1 with marked ST depression in V2

• ST elevation in III > II (Lead III is more rightward facing than lead II and hence more sensitive to the injury current produced by the right ventricle)
  

• The "posterior wall" may not even exist. Source but it does for exam purposes.

- Isolated posterior wall STEMI is uncommon.
- Tall R waves in V1 and V2 are reciprocals of Q waves in the posterior wall.

Post MI prognosis

• Mechanism: inhibits phosphodiesterase, inhibits thromboxane A2 synthesis.
• cAMP - (which is generated by activation of adenylyl cyclase (the green AC in the diagram) )- activates protein kinases.
• Protein kinases like PKA activate many enzymes (and ion channels) which regulate cellular metabolism or myosin light chain kinase which is required for smooth muscle contraction. (Phosphorylation of myosin light chain kinase inactivates it causing smooth muscle relaxation).
• Key Point : PDE inhibitors raise cAMP levels.

Coeliac disease

BCD + PRSTUvW
Bacterial overgrowh, Coeliac disease, Dermatitis herpetiformis
Parasites, Resection, Sprue, Tropical Srpue, Uv = radiation, Whipples

• Prolamins are proteins which have high glutamine and proline content so they don't get digested by pepsin and pass into the intestine.
• Prolamins actually pass through the epithelium and undergo deamination by transglutaminase which makes them more immunogenic.
• CD4 T cells are stimulated and the resulting inflammation causes disease.
• interferon gamma is involved.
• the disease process results in crypt hyperplasia and villous atrophy.
• Increased risk of small bowel lymphoma.
• Malabsorption can cause iron deficiency and folate deficiency.

Symptoms

Complications

• Associated with autoimmune diseases: IBD, [[2022-November#Primary Biliary Cirrhosis / Primary Biliary Cholangitis|PBC]], ILD, CLCD, epilepsy. (Mnemonic: all acronyms)

• gold standard: small bowel biopsy. (Most commonly from duodenum but also from jejunum)
  • Patient needs to be on a gluten containing diet for 6 weeks before serologic or biopsy testing for the tests to yield positive results.
• Serology is very useful : endomysial (IgA ) and tissue transglutaminase antibodies.
• Tissue transglutaminase antibodies (IgA) are first line: NICE
• Anti-gliadin is not recommended.
• Anti-casein is found in some patients.

• Occurs particularly in young adult males, with a male to female ratio of 4:1 Source
• Vector: Culex quinquefasciatus (in SL) but also aedes species and anophelesSource

[!INFO] It takes 1 hour to process 1 unit

• Cryoglobulins are Immunoglobulins and / or complement components which precipitate reversibly in at temperatures below 37°C.
• Cryoglubulins can cause a systemic small to medium vessel vasculitis triggered by cryoglobulin containing immune complexes.
  • Ig bound to Fc portion of polyclonal IgG = (? like Rheumatoid factor which is IgM against Fc of IgG)
  • Type 2 - Monoclonal IgM is bound to IgG and polyclonal IgG; often associated with hepatitis C.(also seen in SLE and Sjogren's, Hep B, HIV etc - i.e chronic viral infections)
    • Glomerular disease is more common in type 2 than type 3. -> membranoproliferative glomerulonephritis
  • Type 3 - Polyclonal IgM is bound to IgG and polyclonal IgG;
  • Type 2 and Type 3 are referred to as mixed cryoglobulins. They are commonly associated with infections, autoimmune diseases, and lymphoproliferative disorders: Hep C is the commonest infective cause.
    eg; digital ischemia, livedo reticularis, skin necrosis, purpura (due to vasculitis) , Raynaud phenomemon - specially with cold temperatures.
    

• Mutations in CDH1 gene causing reduced levels of E-cadherin
• APC gene mutations (adenomatous polyposis coli)
  Gastric cancer has poor prognosis and new treatment modalities are needed.
  Distal cancer incidence as reduced greatly but proximal and GE cancer incidence has increased.
  Lauren classification:
• Intestinal type: Bulkly, glandular cancers: usually adenocarcinoma. Associated with chronic gastritis and metaplasia. This type of cancer is reducing in incidence.
• Diffuse type: infiltrative growth pattern, desmoplastic reaction gives rise to linitis plastica.
• Commonest type is adenocarcinoma comprising 90%.
• Carcinoid tumours:
  Gastrin, produced by G cells of the antral glands promotes growth of gastric adenocarcinoma through cholecystokinin-B receptors which are over expressed in this cancer.
  1. chronic administration of proton pump inhibitors,
  2. atrophic gastritis
• H pylori can cause chronic gastritis leading to metaplasia.
  Types of cancer associated with H. pylori:
• Gastric adenocarcinoma (both diffuse and intestinal types)
• MALToma
  • The stomach is the commonest site of MALT tumours. (mucosa associated lymphoid tissue tumours)
  • Normal stomach doesn't have significant lymphoid tissue but H-pylori infection leads to aggregation of lymphocytes in the lamina propria.
  • Lymphocyte activation leads to follicle formation -> somehow proceeds to MALToma
  • Maltoma: H pylori stimulates H pylori reactive T cells which drive B cell proliferation; The lymphomas are of B cell origin.
    • Early H pylori eradication "cures" the lymphoma.

• Cardiovascular: Mitral valve prolapse.
  • But also MR, TR, Aortic root dilation, aortic dissection
• Valvular dysfunction - MR and AR + coronary aneurysms

📑Management of PCKD

• Manage blood pressure with ACEi / ARB
• Restrict dietary sodium
• Higher fluid intake is recommended. (>3) -> prevents nephrolithiasis and suppresses ADH which may increase cyst growth.
• Tolvaptan - given for high risk patients; proven benefit. (because ADH promotes cellular proliferation). Slows progress of disease. ?does not induce regression? #2020GM-JUL/Q29

[!TIP] Mnemonic: Don't confuse with PSC - PBC has 'cirrhosis' in the name -> liver tissue is inolved -> interlobular bile ducts are involved.
#2016GM-OCT/Q30
enterohaemorrhagic (EHEC) (aka STEC - shiga toxin producing E coli)

But there are actually 5 types.

1. ETEC causes watery diarrhea in resource-limited settings and is commonly found in food and water in areas without adequate sanitation
2. EPEC (enteropathogenic) was the first E. coli pathotype identified as a causative agent of watery diarrhea primarily in infants and young children in resource-limited settings
3. EAEC (enteroaggregative) is a causative organism of acute and chronic watery diarrhea in resource-limited and resource-rich regions
4. EHEC/STEC produces Shiga-toxin and includes serotypes O157:H7, as well as others
5. EIEC-induced diarrheal illness is uncommon due

• Source

Hook worm

Necator americanus ("American murderer")
and ancylostoma ceylonicum

• The adult worms embed into the mucosa with the anterior part and live in the caecum and ascending colon, shedding thousands of eggs per day. Their lifespan is about 1 year.
• Commonly asymptomatic

🔖Neurocysticercosis

#2022BSQ-OCT/Q5

cyst	Scolex

[!TIP] Mnemonic :"Solium polium" - solium = pork tapeworm.
Only pork tape worm causes cysticercosis
Taeniasis - tape worm in the intestine.

• Humans eat pig meat
• Pigs eat human poop.
• If humans eat human poop (own poop (autonifection) or someone else poop)-> neurocysticercosis

• ONLY TAENIA SOLIUM causes CYSTICERCOSIS.

• Probably the most common parasitic infection of the CNS.

• Pigs -> intermediate host,

• Humans -> definitive host.

cysticercosis results from humans acting as 🔖accidental intermediate hosts for the parasite

[!INFO] Humans are the only definitive hosts for Taenia saginata, solium and asiatica.

[!INFO] Humans eat pig meat -> taeniasis, Humans eat pig poop -> cysticercosis
Ingesting uncooked pork -> ingestion of cysts in pig muscle -> intestinal tape worm infection in the human.
Ingesting eggs in faeces from infected human -> cysticercosis -> possible neurocysticercosis.
In cysticercosis, eggs hatch into larva which migrate through the host body into various tissues.

[!INFO] Phases of neurocysticercosis :
There are two forms; parenchymal (>60%) and extraparenchymal.

• Phase 1: viable phase -> parasite is implanting in tissue; no significant inflammation. Cyst may secrete immunosuppresive chemicals. Can last years or be very short.
• phase 2: early inflammatory stage: When ability to evade host response is lost. Inflammation begins. But parasite remains viable.
• Phase 3: host response begins eradicating parasite. Cyst degenerates.
• phase 4: non viable phase -> calcified granuloma formation.

• Now found that most infections are asymptomatic. However, people infected with cysticercosis usually present due to the neurological symptoms.
• Seizures are the commonest presentation.
• Diagnosis: Combination of imaging AND serology (antibody tests) are required because there are situations in which only one of the two modalities will show positive results.
  • Or serum PCR also. Brain biopsies can also be used.
  • There is no peripheral esoniphilia.
• Imaging : MRI or CT, Serology: Immunoblot / enzyme linked assay
• Treatment:
  • Treatment of neurological symptoms with anticonvulsants, reducing cerebral oedema, intracranial pressure etc is the main concern.
• Then, cysts are treated if required.
  • Calcified cysts are dead; antihelminthic therapy won't benefit the patient.
  • Live cysts: Antihelminthing treatment must be combined with steroid which penetrates the BBB (Dexamethasone) to lessen the inflammatory response elicited following death of the parasite.
    • i.e antiparasitic Rx. is required for phase 1,2. But the problem is, multiple cysts can be at different phases.
• Treatment:
  • Praziquental and albendazole.
    • Albendazole only for few cysts. Praziquental for more cysts and complicated disease.
  • There may be a risk of seizures when cysticercosis is treated with these drugs.
  • Eye evaluation is essential before treatment because treatment can worsen eye neurocysticercosis.

🔖Granuloma formation and patterns

A good detailed Source

[!TIP] overall summary
Granuloma formation is a histologic pattern of chronic inflammation.
Macrophages and tissue macrophages (histiocytes) usually form granulomas in order to eliminate an antigen which cannot be removed by a single macrophage.

• However, sometimes, granulomas are formed in the absense of an antigen, due to autoimmune diseases.
  When a macrophage encounters something it cannot phagocytose, it secretes mediators (?cytokines) which promote migration of other macrophages to the site.
  When many macrophages arrive at the site, they collectively undergo changes which allow them to form functional granulomas:

1. Epithelialization : where the cell membranes begin to interdigitate.
2. Giant cell formation.
3. This is when multiple macrophages fuse to form a giant cell with multiple nuclei.
   In addition, other types of immune cells are also recruited.

The type of immune cell that is recruited and the cytokines secreted by it will determine how the granuloma 'matures'.

Specially, Th cells have a significant role to play here.
When some granulomas mature, the central macrophages undergo necrosis ->

• This is called a necrotizing granuloma and is charachteristic of certain diseases.
  Other granulomas will undergo fibrosis. Also characteristic of some diseases.
  The main patterns that we are concerned with are caseous vs non caseous necrosis and necrotizing vs. non nectrotizing granulomas.

[!INFO] Exerpt from the summary of the article above:

• Granuloma macrophages can undergo different types of specialized differentiation.
• Multiple additional types of cells can be recruited in the granuloma and influence its structure and function.
• Granulomas can form in response to large and small particles, which can be infectious agents or nonliving objects.
• Many granulomas occur in the context of inflammatory and autoimmune diseases in the absence of a known antigenic trigger.

Granuloma formation is a histologic pattern of chronic inflammation.
The particular pattern can suggestive of a particular disease

The pattern of inflammation can be classified in many ways. (necrotizing or not / Suppurative or not etc.)
This corresponds to the features of the granuloma after 'maturation'.
The prototypes are

• necrotizing - myocobacterial granulomas
  • This occurs when granuloma macrophages undergo necrosis.
  • eg Tuberculous and other infectious granulomas (fungal ones where the pathogen is intracellular). Source
  • Other examples of necrotizing granulomas: rheumatoid nodules and granulomatosis with polyangiitis and occasionally those in sarcoidosis.
• non-necrotizing - sarcoidosis.
  • Why these macrophages don't undergo necrosis is non known.
  • Examples: beryllium granulomas, Crohn's granulomas and sarcoidosis.

monocytes in blood -> become macrophages in tissue (aka histiocytes)
histiocyte = tissue macrophage

[!INFO] Granuloma formation: Overview
Granulomas are formed when individual macrophages can't eliminate an antigen.
Then antigen presenting cells in the tissue recruit more macrophages from the circulation into the tissue.
Macrophages all clump around the antigen forming a granuloma.
The macrophages undergo a process called epithelialization where they take on the appearance of epithelial cells.
Their membranes begin to interdigitate and the nuclei swell.
Some of the macrophages will fuse to form Langhans giant cells.
The structure of the granuloma differs based on the triggering antigen.
In Tuberculosis, interferon gamma is a mediator of granuloma formation.
Other mediators like TNF-alpha are important in the formation of granulomas.

🔖Granulomatous diseases

1. Naked granulomas - only sparse lymphocytic infiltrate at margin of granuloma; is a typical sarcoid lesions.
2. Suppurative granulomas - have neutrophils at the center.
   1. Fungal causes
   2. Bacterial causes
   3. Atypical mycobacteria
   4. Pyoderma gangrenosum
   5. Parasitic : leishmaniasis
3. Tuberculoid granuloma - caseous necrosis
   1. Usually in TB. Not in leprosy.
4. Foreign body granulomas
   1. Berylliosis
   2. Silicosis
5. Necrbiotic - contains altered collagen in the center. Also has acellular substances in the center.
   1. Divided into red and blue granulomas depending on the stain colour.
      1. Eosinophils are red.

Neutrophilic dermatoses

• Pyoderma gangrenosum
• Sweet syndrome
• Behcet disease

Pyoderma gangrenosum

Source

Pyoderma gangrenosum (PG) is a rare neutrophilic dermatosis that presents with rapidly developing, painful skin ulcers hallmarked by undermined borders and peripheral erythema. Epidemiological studies indicate that the average age of PG onset is in the mid-40s. Source

• Acute onset
• Purpule
• Undermined edge
• Painful
• Multiple ulcers

Pathergy is a feature.

[!INFO] Pathergy:
Pathergy is an exaggerated skin injury occurring after minor trauma such as bump, bruise, needle stick injury. A more severe injury, such as a surgical procedure, can result in persistent ulceration in a patient with pathergy. It typically occurs in patients with Behcet disease.
Pathergy occurs in :

• Sweet syndrome
• Behcet-disease
• Pyoderma ganrenosum

DD for neutrophillic dermatosi: Sweet syndrome

Biopsy: INTENSE neutrophilic infiltrate with no evidence of infection or vasculitis.

#2017GM-APR/Q10

Associated diseases are

• Rheumatoid arthritis
• SLE
• Ulcerative colitis(5%) and Chron's(1%) (to a lesser extent)
• Solid organ tumours (breast cancer, gastric, renal, lung etc)
• Haematologic tumours:
• Granulomatosis with polyangitis

Treatment: steroids and immunosuppresants.

Sweet syndrome:

aka acute febrile neutrophilic dermatosis.

• Dermal neutrophilic infiltration
• Plaques and papules
• Fever
• Peripheral neutrophilia.
• Behcet
• Monoclonal gammopathy

🔖Metastasis in neoplasia

#2022BSQ-OCT/Q2

Routes of malignant spread

1. Seeding of body cavities : Typical of ovarian CA
2. ❗Lymphatic spread : more typical or carcinoma
3. Haematogenous spread: more typical or sarcoma.
   1. Arteries are less easily penetrated than veins. ❗Mets occur along venous drainage.
   2. All portal drainage goes to the liver; all caval blood flows to the lung -> these capillary beds are the main sites of metastasis in ❗haematogenous metastasis.
4. ❗Thyroid and prostate CA metastasize via the paravertebral plexus -> vertebral metastases.
   1. bone metastases are more frequent in follicular and medullary thyroid cancers
5. ❗Renal and hepatic CA like to grown inside veins:
   1. ❗Renal - renal veins and IVC
   2. ❗Liver hepatic veins and IVC
6. Path of venous drainage alone doesn't account for the distribution of particular metastatic tumours; Some tumours have a propensity to metastasize to particular organs. This may be due to chemoattraction or expression of tissue specific adhesion molelcules by tumour cells.
   1. ❗prostatic carcinoma preferentially spreads to bone,
   2. ❗bronchogenic carcinomas tend to involve the adrenals
   3. and the brain, and neuroblastomas spread to the liver and bones.

🔖Brain tumours

Primary brain tumours are either

1. Glial tumours - airising from glial cells
2. Non glial - arising from everything else; nerves, blood vessels, glands etc.

Thyroid cancer

#2022BSQ-MAY Q27
Source:Medscape


Follicular cells : Papillary, follicular and anaplastic CA.
Parafollicular C cells : Medullary CA. (C cells are neuroendocrine cells and they produce [[Hormone Physiology#Calcitonin|Calcitonin]]).

Differentiated thyroid cancers

[!INFO] Hot nodules are almost always noncancerous
However, the majority of thyroid nodules scanned are (Approximately 95 percent) are cold.
Most cold nodules are due to benign processes (>90%)
Cold nodules have an approximately 5% risk of being cancerous.
However, HOT nodules are almost never cancerous.

Both papillary and follicular CA are 3 times commoner in women.
Follicular develops at an older age.

Thyroglobulin is produced by differentiated thyroid CA. It can be used as a marker of recurrent after total thyroid ablation.

Papillary CA:

• Multifocality is a common pathological feature of PTC.
• Papillary carcinoma is a slow-growing tumor (has good prognosis) that arises from the thyroxine (T4)- and thyroglobulin-producing follicular cells of the thyroid.
• The cancer cells are TSH sensitive and take up iodine. They produce thyroglobulin in response to TSH stimulation
• Papillary CAs form non functional nodules. - Cold on scintigraphy.
• Histology: ❗Unencapsulated; Consist of neoplastic epithelium growing on fibro vascular cores.
• Special nuclear features : emtpy nuclei ('orphan annie')
• Ability to invade adjacent lymphatics is a key feature.
• They tend to metastasize to the cervical lymph nodes.
• Haematogenous spread is rare but most common distant metastasis is to the lung.
• Factors which make a papillary CA high risk : Hx of head and neck radiation, male sex, age < 18 or > 55, + other obvious ones.

• Psammoma bodies are seen in papillary CA. (concentric, lamellated microscopic calcium deposits. They can be seen in other cancers and some benign lesions as well)

Follicular CA

Are also usually cold nodules on radioiodine scan.
Commoner in iodine deficient areas.

Histology: encapsulated.
Follicular cells have a solid, trabercular or follicular growth pattern.
No characteristic nuclear features.
Differentiated from benign adenomas by

1. capsular invasion
2. vascular invasion

They arise from the follicular cells of the thyroid. The neoplastic cells are TSH sensitive as well, taking up iodine and producing thyroglobulin—a feature that is exploited diagnostically and therapeutically

Follicular carcinomas have less tendency for local metz (nodes) but higher risk of distant mets.

Distant mets for both types occur to lung and bone.

Hurthle Cell carcinoma

Hürthle cell carcinoma is a rare, more agrressive variant of follicular carcinoma. 5 year survival is 50 - 60%.
Makes up 2-3% of all thyroid malignancies.
Composed of distinct looking polygonal cells with acidophillic cytoplasm.
Associated with RAS mutation and RET/PTC oncogene.

[!INFO] Hurthle cells are seen in non malignant conditions as well
Hurthle cells are clasically seen in

• Hashimoto thyroiditis
• multinodular hypoplasia
• lymphocytic thyroidis
• Source

Medullary thyroid Cancer (MTC)

2-3% of thyroid CA.
They are associated with familial MTC (FMTC) syndromes.
So much so that there is a clinical distinction between identification of patient familial MTC and diagnosis a new sporadic MTC.

Parafollicular C cells produce calcitonin -> elevated calcitonin is diagnostic of MTC.
Inheritance of all familial forms of MTC and MEN2 are #autosomalDominant .
RET proto-oncogene mutations are seen in all MTC syndromes.

Approximately 80% of individuals with a RET genetic variant will develop medullary thyroid cancer at some point in their lives.

FTMC is a subtype of MEN2. FMTC patients have less probability of the other cancers of MEN2 but higher probability of medullary thyroid CA.

Familial cases are multifocal and bilateral.
Sporadic cases are unifolcal.

Histology:

• unencapsulated.
• Focal calcifications are present.
• Characteristic deposition of amyloid is seen in the tumour. <- A unique features in thyroid malignancy.
• C cell hyperplasia is unique to familial cases.

Treatment:
Lymph node metastasis is common.
Total thyroidectomy with lymph node clearance is done.
Prophylactic thyroidectomy is done in children diganosed with MEN2 syndromes.

MEN2 is divided into three subtypes: type 2A, type 2B and Familial Medullary thyroid carcinoma (FMTC).

1. MEN2A - pheochromocytoma, hyperparathyroidism.
2. MEN2B - MTC, phaechromocytoma, marfanoid habitus and galngioneuromatosis.
3. FMTC - only MTC. (low risk of others)

Multiple Endocrine neoplasia syndromes

In treatment of MEN, to avoid intra op hypertension, resection of pheochromocytoma should be done before MTC resection.

[!TIP] Mnemonic for MEN syndromes
පා පා පි
පා මේ ෆි
මා මේ ෆි

Anapalstic thyroid CA

[!WARNING] A very, very bad cancer!
It is rare but has the worst prognosis of all thyroid CAs.
Occurs in older adults (60-70) -> older adult with a thyroid nodule could have a dangerous thyroid CA.
1 year survival is a dismal 20%. Median survival is 5-6 months.

Anaplastic CA grows rapidly. Many patients present with local invasion (unresectable tumours) or cervial lymph node metastasis.

On histology, the tumour retains feature so epithelial cells (presence of desmosomes) but there are large areas of necrosis and bleeding. There is high mitotic activity.

Bone tumours

• In adults, bone mets are far more common than primary bone tumours.

• Bone is the 3rd commonest site of metastatis next to Lung and liver.

• Prostate and breast cancer (BC) are responsible for the majority of the skeletal metastases (up to 70%).

• Other sources of bone mets : thyroid, renal cell carcinoma, lung cancer, melanoma

Bone metastasis

Bone mets are commonest in spine, pelvis and thigh.

Osteolytic :

1. Multiple myeloma
2. RCC
3. melanoma
4. NSCLC
5. Non Hodgkin Lymphoma
6. thyroid cancer
7. Breast cancer

Osteoblastic:

1. prostate cancer,
2. carcinoid,
3. small cell lung cancer,
4. Hodgkin lymphoma
5. medulloblastoma.

Mnenomic for sclerotic bone lesion:
#2023BSQ-NOV/Q12

• 6 bees lick pollen
  
  Ignore breast in this list!

Regarding prostate CA:
Pathologic fractures do occur, although they are generally less frequent than in cancers with predominantly osteolytic disease
Source

Multiple myeloma – The classic bone lesions in multiple myeloma are purely osteolytic due to increased bone destruction and suppressed bone formation.

Prostate cancer – Males with bone metastases from prostate cancer predominantly have osteoblastic (aka sclerotic) lesions with increased numbers of irregular bone trabeculae. Simultaneously, osteoclastic action is also increased.

Breast cancer - The great majority of breast CA produces osteolytic bone lesions, osteoblastic areas are also usually present

Renal cancer also commonly spreads to bone.

Atherosclerosis

#2022BSQ-OCT/Q08
Plaques are raised lesions in the blood vessel.
Filled with cholesterol and cholesterol esters.
#2020BSQ-JUL/Q32

Overview of atherosclerosis

[!INFO] Response to vessel injury
Vessel injury of any cause produces the same stereotyped response. Intimal thickening is a stereotypical response to vessel injury.
Mechanism: Intimal injury stimulates migration of smooth muscle cells from the media OR from circulating precursors!. They arrive in the intima, undergo mitosis and produces extracellular matrix, forming a 'neointima'. This is analogous to scar formation elsewhere. Neointimal smooth muscle cells are non contractile but can undergo mitosis and greater synthetic capacity. This altered activation of neointimal smooth muscle cells is driven by cytokines produced by platelets, macrophages, endothelial cells and circulating complement and coagulation factors. Cytokines involved are PDGF, FGF, TGF-alpha (Platelet derived growth factors, Fibroblast growth factors, TGF-alpha).
Removal of the harmful stimulus will revert the phenotype of neotintimal muscle cells to their non proliferative (medial smooth muscle is non proliferative) state but the thickening they have produced is irreversible.
Intimal thickening is also a normal part of aging but because of outward remodeling, does not narrow vessels.

Risk factors for atherosclerosis have roughly multiplicative effects. 2 factors -X2 risk, 3 factors X7 risk.
Risk factors:
Dietary:

• High intake of saturated fats raises lipid levels.

• Trans unsaturated fats found in margarine are bad.

• Omega 3 fatty acids in fish are good.

• Exercise and moderate consumption of ethanol raises HDL levels.

• CRP produced by 'cells in the plaque' increase adhesiveness of endothelial cells and CRP independently and strongly correlated with risk of infarction.

• Lipoprotein a increases risk.

• "The internal elastic lamina is a fenestrated sheet that forms the boundary between the intimal and medial layers, influencing both its mechanical and mass transport properties"

• Neovascularization produces vessels which can rupture into the plaque and cause haemorrhage into it.

Atherosclerosis requires two factors

1. Endothelial dysfunction
   1. Involving altered gene expression (eg. incr. adhesion molecules) and increased permeability of endothelial cells.
   2. This allows migration of blood monocytes into the intima where they become macrophages.
2. Increased lipids in the blood
   1. Cholesterol and it's esters are found inside plaques. They stimulate chronic inflammation in the intima in the presence of macrophages.

Anything that exacerbates these two factors will promote atherogenesis.

1. Endothelial damage and dysfunction
   1. Smoking, hypertension, flow turbulence, some infection, ?toxins and drugs
2. Hyperlipidaemia
   1. Any condition increases blood lipid levels ?Which lipids exactly - not HDL.

In the presence of lipids within the intima, macrophages become activated. When they 📑engulf lipids, they become foam cells.
Cytokines secreted by macrophages stimulate altered function and growth of smooth muscle cells of the media.
📑Smooth muscle cells proliferate and take on fibroblastic roles.
Smooth muscles + collagen produced by them form the fibrous cap of the plaque.

Plaques can

1. obstruct vessels
2. rupture -> thrombosis
3. weaken the media -> aneurysms

Factors which make a plaque unstable:

1. Thin fibrous cap
2. Increased foam cells
3. Increased lipid content etc.

[!INFO] The response to injury hypothesis of atherosclerosis

1. Views atherosclerosis as a chronic inflammatory process.
2. There is interaction of lipoproteins, macrophages, T lymphocytes to cause progression of the lesion
3. Main components of atherosclerosis:
4. Endothelial injury with ⬆ adhesiveness and ⬆ permeability - the main component. Atherosclerosis begins at intact but dysfunctional endothelium.
   1. Endothelial dysfunction is promoted mainly by altered haemodynamics and hypercholesterolemia.
      1. Haemodynamics: Turbulence; as occurs at ostia, branch points and posterior wall of the aorta. Laminar flow is protective via gene induction.
      2. Hypercholesterolaemia - 1) directly causes endothelial dysfunction, 2)Promotes inflammation by formation of oxidised LDL and cholesterol crystals
   2. Dysfunctional endothelium promotes adhesion of inflmmatory cells including macrophages (which engulf LDL to become foam cells) and T lymphocytes (which set up chronic inflammation).
5. Platelet adhesion
6. Monocyte / macrophage adhesion and adtivation
7. lipid and lipoprotein accumulation
8. Smooth muscle cell recruitment by mediators produced by platelets, macrophages
9. Smooth muscle cell proliferation.

• The earliest lesion is a Fatty streak. Componsed of Foam cells but not raised.
• Aortic fatty streaks are present in all children.
• Coronary fatty streaks form during adolescence.
• Not all fatty streaks progress to atherosclerotic plaques.
• Some are converted to 'mature atheroma' by smooth muscle proliferation and matrix synthesis.
  • Mature atheromas have CELLS, MATRIX and LIPIDS.
• Key feature of atherosclerotic plaque is intimal thickening and lipid accumulation.
  • They are white / yellow raised lesions.
  • They involve only a part of the cirumference of the wall. ('patchy')
  • Frequency of atheroma formation
    • Infrarenal aorta > Coronaries > poplitieal arteries > internal carotid > Circle of willis
    • Mnemonic: A Clever Parrot Imitates Words
    • 
    • Upper limbs, renal arteries and mesenteric arteries are usually spared.
    • Lesions at various stages coexist in the same vessel.

Morphology:

• The shoulder of the plaque is more cellular.
• Acellular components are fibrin, collagen and proteoglycan.
• Cholesterol clefts are seen because cholesterol crystal present in plaques are removed by processing.
• Periphery of plaques show neovascularization!
• Plaques progressively enlarge. They can undergo calcification.

The majority of plaque ruptures occurs in the proximal and middle of coronary arteries and distal ruptures are rare.
Source

🔖Pancreatic physiology

#2022BSQ Q24

Secretin and CCK are endocrine hormones.
Secretin - role is to neutralize stomach effluent

• peptide hormone
• produced by S cells of duodenum and brain
• inhibits gastrin release -> to reduce stomach acid production
• Stimulates pancreatic secretion of fluid and bicarbonate
  Cholecystokinin - promote pancreatic enzyme secretion, and gall bladder contraction.

Secretin stimulation test: Although secreting physiologically inhibits gastrin secretion, in the presence of a gastrinoma, secretin paradoxically increases gastrin secretion. This is the basis of the secretin stimulation test for gastrinoma.

🔖Selected gastrointestinal regulatory peptides

#2022BSQ-OCT/Q24

See table 32.4 K and C.
Secretin glucagon family
Vasoactive intestinal peptide (VIP) -> Secreted by enteric NERVES -> Neurotransmitter, Stimulates insulin release, splanchnic vasodildation and intestinal secretion of water and electrolytes; also relaxes smooth muscles, including the lower esophageal sphincter and colon
Mnemonic: VIP readies the stomach and gut receival of food.

Glucose dependent insulinotropic polypeptide - GIP - - From duodenum, gastric antrum and ileum - stimulated by intraduodenal glucose -> incretin effect. (produced by K cells)

GLP-1 - The main actions of GLP-1 are to stimulate insulin secretion (i.e., to act as an incretin hormone) and to inhibit glucagon secretion, to limit postprandial glucose rise. Secreted by L cells in the ileum and colon.

Humans have almost no L cells proximal to the ligament of treitz (i.e in the duodenum) Source

Secretion is likely triggered by glucose in the duodenum as well as the rest of the gut as well. Source

GLP-1 physiology

Source
Only a small percentage of the produced GLP-1 reaches the liver and systemic circulation because of the action of DPP-IV.

[!TIP] Mnemonic: All of these hormones generally cause changes which promote digestion and absorption except for somatostatin

Somatostatin: somatostatin decreases endocrine and exocrine secretion and blood flow, reduces gastrointestinal motility and gallbladder contraction, and inhibits secretion of most gastrointestinal hormones.

Secretin: physiologic role increases pancreatic bicarbonate secretion and inhibits gastrin production. But in gastric CA, administration of secretin causes increased gastrin production. (paradoxically)

🔖Bilirubin physiology and elevations

[!INFO] Elevated urobilinogen levels
#2020BSQ-NOV/Q04
Urobilinogen levels rise with increasing bilirubin production.
"Elevated urobilinogen levels may also be seen when the liver simply cannot remove urobilinogen from the portal venous blood, as occurs in severe liver disease, such as cirrhosis." - Source

[!INFO] Significance of active conjugated bilirubin secretion from hepatocytes
The active secretion of cojugated bilirugin into bile cannaliculi is rate limiting. But uptake of unconjugated bilirubin is very efficient.
Therefore, hepatocytes near the supplying veins will take up all the unconjugated bilirubin but may not be able to excrete all of it into the bile. Therefore, they reexcrete it into the sinusoids so that down stream hepatocytes can reuptake this conjugated bilirubin and help to excrete it into the bile canalliculi.
I.e more hepatocytes are recruited for excretion.
The transport proteins requried for reabsorption are affected in Rotor syndrome -> leads to conjugated and unconjugated hyperbilirubinaemia.(mostly conjugated)

Classification of causes of hyperbilirubinaemia

[!TIP]
Note how all the intrahepatic causes of jaundice cause conjugated hyperbilirubinaemia.
?? are the only causes of unconjugated hyperbiliribunaemia CN , Gilbert and haemolytic anaemias?

[!INFO] DDx of conjugated hyperbilirubinaemia
And this table which Medscape made incredibly hard to copy.

Causes of unconjugated hyperbilirubinaemia

From Harrisons

1. Haemolysis
2. Ineffective erythropoiesis
3. Defective conjugation - Criggler najjar and Gilbert
4. Acquired conjugation defects
   1. It's possible in cirrhosis but usually, "conjugation is better preserved than other aspects of bilirubin metabolism like canalicular secretion".
   2. Gentamicin can inhibit UGT1A1 -> unconjugated hyperbilirubinaemia

🔖Complement system overview

#2019BSQ-OCT/Q54

The complement system consists of a set of plasma glycoproteins.Source.

What follows are several images of how the complement system works;
Source

Main functions of the complement proteins

[!INFO] Functions of complement

• Promote inflammation through C3a, C4a and C5a
• Recruit cells (through chemoatractants)
• Kill targeted cells (bacteria)
• Solubilitze antigen-antibody complexes and remove them from circulation

Source

[!INFO]

C3a is an anaphylatoxin
C3b is an opsonin (it binds to foreign molecules) -> it tags microorganisms as foreign.

Activation of the 3 complement pathways

Classical pathway

Evolutionarily the newest but first to be discovered.

• This is activated by activation of the C1 complex. (which consists of q,r,s subunits; therefore called C1qr2s2)
• Activation of C1 complex occurs when C1q binds IgM or IgG. Only one IgM is require but six IgG molecules are required.Source-Wiki
• Autocatalytic activation of C1r and C1s in turn cleaves C4 and C2 into larger (C4b, C2a) and smaller (C4a, C2b) fragments.
• C4bC2a assembles on pathogen surfaces and forms the C3 convertase of the classical pathway.
• the classical pathway has a major role in clearing antigen antibody complexes and debris from dying cells.

Alternative pathway

Evolutionarily the oldest
Basically, C3 is constantly being hydrolysed at low levels to form C3b but this is inactivated rapidly. If the C3b happens to bind to a pathogen, it become protected from inactivation and can trigger subsequent cascade activation.
The alternative pathway does not require antibodies.
It is triggered when C3b binds to bacterial polysaccharides and other endotoxins.

More details:

The alternative pathway of complement activation depends on spontaneous hydrolysis of C3 in plasma leading to the formation of C3 (H2O). This molecule binds to factor B. Subsequent activation by factor D results in the formation of C3 (H2O) Bb. This complex cleaves additional C3 to C3a and C3b constantly and at a low rate. In the presence of an activating surface (e.g. a bacterial wall), C3b is protected from inactivation by regulatory proteins like factor I and H. As a result, a more active alternative pathway C3 convertase - called C3bBb- is formed, which is further stabilized by properdin.Source

Then, the C3b particles formed by both pathways above goes on to form the C5 convertase by combining with various other complement factors.

[!INFO] C5 -> C5a (Most potent anaphylatoxin ) + C5b (initiator of MAC)

Diseases of complement deficiency

Source

[!TIP] Mnemonic :

• some of these may help
• C1-INH - Hereditary aNg1odema (flipped HN1)
• C3 three rhymes with B(ee) for bacterial infections
• C5 – think five fails to thrive – Leiner's disease – malabsorption, diarrhoea, wasting, and dermatitis in children
• C5-9 – MAC – MeniNINEtis or MACingitis

• Alternative pathway

  • repeated severe infections from birth. (Streptococcus pneumoniae and Hemophilus influenzae)
  • properdin - the only X linked complement component. Classic history is family history of males dying if meningitis.

• classical pathway

  • predisposes to autoimmune diseases like SLE
  • C2 efficiency is the commonest deficiency in Europeans - causes haemophilus and streptococcus infections.

• MBL pathway

  • deficiency is very commingled and may not be clinically significant.

🔖Causes of increased CPK

#2022BSQ-OCT/Q31
CPK = CK.
Creatine Kinase is a catalyst for the formation of ATP from ADP via transfer of phosphate from creatine phosphate (which is an energy reservoir for muscle.
It is a very good indicator of muscle breakdown and it's progression.
CPK is eliminated by the ❗Reticuloendothelial system❗. Serum level isn't elevated in kidney disease.

3 isoforms

• Skeletal muscle - 99% CK MM

• CK-MB = Usually in cardiac muscle. Can also be elevated in elite athletes and normal people after strenuous exercise (i.e can produce false +ve for MI)

• CK is usually elevated in myopathies. => there are different types of myopathies

  • Inflammatory myopathies - polymyositis / dermatomyositis
  • Drugs - colchicine (gout), antimalarials, statins, alcohol
  • Metabolic myopathies - carnitine palmitoyltransferase deficiency, Muscle phosphorylase deficiency (McArdle's disease)
    • McArdles disease - #autosomal-Recessive , exercise intolerance in childhood followed by cramps and myoglobinuria
  • Endocrine myopathies - hypothyroidism, acromegaly
  • Periodic paralyses - hours to days of muscle weakness with sharp rises of CPK; due to muscle membrane refractoriness secondary to ion shifts.
  • Neuroleptic malignant syndrome
  • Malignant hyperthermia - usually follows use of anaesthetic agents.

• Can also be elevated in a few non myopathic conditions

  • Exercise
  • Iatrogenic muscle injury
  • ❗motor neuron disease❗
  • Asymptomatic elevation in CK

🔖Urine cultures

We want to get urine samples which contain bacteria which have managed to enter the bladder. (bacteria colonize the distal urethra and genital mucosa)
Theoretical best sample is first voided urine of the day as bacteria have had time to multiply overnight and it is also the most concentrated sample.
Suprapubic taps should yield sterile urine in a healthy patient.

Prostatic massage should be done prior to urine sample correction in suspected if chronic bacterial prostatis is suspected. ❗Massage should be avoided in acute bacterial prostatits -> risk of bactiraemia!

Sample is cooled until it is sent to the lab to prevent bacterial multiplication affecting the colony count.

Urine microscopy

pyuria

8 cells / microL = 2-5 cells per High power Field.
Very high associated with urinary infection.

• bacteuria without pyuria -> usually means colonization rather than infection. (unless of course, patient is symptomatic)

White blood cell casts - renal infection = could be pyelonephritis.

Causes of sterile pyuria:

• False -ve for bacteria
  • Contamination with antiseptic
  • Atypical pathogens - Chlamydia, Ureaplasma urealyticum, or tuberculosis
• False +ve for leukocytes
  • Contamination with vaginal leukocytes
  • Chronic intersitial nephritis - omeprazole is a cause.
  • Nephrolithiasis
  • Uroepithial tumour
  • Intrabdominal inflammation adjacent to the bladder

Cardiac action potentials

see [[SaltatoryConductionMechanism.png]]

Cardiac action potentials

![cardiacActionPotentials.png](cardiacActionPotentials.png)

Source: CVS physiology website.

Electrolyte effects on ECG

ECG changes in hyperkalemia :

#2020SBR-NOV/19
#2020BSQ-JUL/Q02

The pathophysiology of changes in hyperkalemia includes

• acceleration of terminal repolarization (causes T wave abnormalities)
• Depression of conduction between adjacent myocytes -> Prolongation of PR and QRS duration. Source

Boradening of the QRS complex is a feature (although not mentioned in the table below) Source

In hyperkalemia, ECG changes progress from peaked T-waves to widened QRS and eventually to ventricular tachycardia, fibrillation or pulseless electrical activity arrest.  These progressive changes can correlate with rising potassium levels. For example, peaked T waves might correspond with a potassium level of approximately 6 mmol/L, whereas cardiac arrest generally occurs at higher levels.

Management of hyperkalemia

#2023SBR-NOV/Q24
read in K and C

Emergency: Calcium gluconate

Tall tented t waves - PR prolongation - Broad QRS - Sine wave pattern - asystole, VT, VF

Acute: Insulin + dextrose

Requires 1 - 2 hourly monitoring of plasma glucose.

Subacute management: Potassium binders

• Newer ones:
• Older ones are calcium resonium

Hypokalemia

[!INFO] Mnemonic: Opposite of the hyperkalemic changes

EKG changes can include

• increased amplitude and width of P wave,
• T wave flattening and inversion,
• prominent U waves and
• apparent long QT intervals due to merging of the T and U wave and
• 'mild' ST depression.

The 'classic findings' are

• Diminished T wave, increased U wave, ST depression Source

The U-wave is a deflection following the T wave. Potassium levels that are critically low (<1.7 mmol/L) can lead to torsades de pointes or “twisting of the points”, a polymorphic ventricular tachycardia.

[!INFO] 📑U wave

• mechanism of generation isn't clearly identified
• normal u wave is concordant with the t wave
• it is smaller than the t wave (1/3 size)
• it's size increases with decreasing hear rate
• Best seen in V2 and V3.

Torsades de Pointes

[!INFO] Definition of Tosade de pointes
Torsade is defined as the combination of polymorphic ventricular tachycardia plus a prolonged QT-interval.
Source
Polymorphic VT is defined as ventricular tachycardia with varying QRS amplitute.

Pathophysiology: QT prolongation predisposes to 'after depolarizations' which can produce TdP

also [[torsadesDePointes.png]]

• Life threatening arrhythmia
• This is a type of polymorphic ventricular tachycardia.
• QRS morphology changes from beat to beat like in any polymorphic VT.
• Is inherently unstable -> either terminates within spontaneously or degenerates to VF
• Associated with acquired or congenital prolonged QT.
  • for TdP to be diagnosed, the patient must have evidence of QT prolongation.
• Can occur in hypokalemia
• Group Ia antiarrthmics which prolong QT should never be used! (basically, disopyramide is contraindicated) [[Cardiology MCQ discussion#Antiarrhythmic drugs|Antiarrhtymics]]

Causes of QT prolongation:

Management

1. Magnesium sulfate bolus (4g of MgSO4) even if Mg level is normal
2. Correct all electrolytes
3. Stop all QT prolonging medications
   1. Quinidine, disopyramide, flecainide, haloperidol, chlorpromazine, TCAs + many others
4. Amiodarone is the drug of choice for for treatment of haemodynamically unstable VT.
5. Verapamil should never be used in VT - ?why
   F

Hypercalcaemia

The most common EKG finding associated with hypercalcemia is shortening of the QT interval. In severe cases, Osborn or J waves might be seen or ventricular fibrillation might ensue. Recognition of these EKG findings can prompt urgent treatment.

Hypocalcemia 🡫

The most common finding on EKG in patients with hypocalcemia is a prolonged QT interval.

https://www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.105.166563

doi.org/10.1016/0002-9149(63)90255-8

Hypermagnesaemia

#TODO

Hyponatremia and hypernatremia have no effect on the ECG.

Increased (hypernatremia) and decreased (hyponatremia) sodium levels do not have any effect on the ECG, nor cardiac rhythm, or impulse conduction. Source

🔖Tumour markers

#2021BSQ-JUL/Q31

Cholangiocarcinoma

• cholangiocarcinoma: Bile duct cancer may cause high levels of carcinoembryonic antigen (CEA) and CA19-9 in the blood.
• Cholangiocarcinoma does not produce AFP. Source
• Cholangiocarcinoma mimics primary sclerosing cholangitis clinically and on imaging;
  • High CEA and CA19-9 make cholangiocarcinoma more likely. Source

[!TIP] GPT answer:
Certainly! Here is a list of common tumor markers and the tumors they are commonly associated with:

1. Prostate-Specific Antigen (PSA) - Prostate cancer
2. Carcinoembryonic Antigen (CEA) - Colorectal cancer, pancreatic cancer, lung cancer
3. Alpha-fetoprotein (AFP) - Liver cancer, germ cell tumors, particularly testicular cancer
4. CA-125 - Ovarian cancer (CA = carbohydrate antigen)
5. CA 19-9 - Pancreatic cancer, colorectal cancer
6. CA 15-3 - Breast cancer
7. CA 27-29 - Breast cancer
8. Human Chorionic Gonadotropin (hCG) - Germ cell tumors, particularly testicular cancer, ovarian cancer, ?lung CA
9. Calcitonin - Medullary thyroid cancer
10. Thyroglobulin - Thyroid cancer (papillary and follicular)
11. Neuron-Specific Enolase (NSE) - Neuroendocrine tumors, small cell lung cancer
12. Chromogranin A - Neuroendocrine tumors
13. S-100 Protein - Melanoma, neuroendocrine tumors
14. Human Epidermal Growth Factor Receptor 2 (HER2) - Breast cancer, gastric cancer
15. Epidermal Growth Factor Receptor (EGFR) - Non-small cell lung cancer, colorectal cancer
16. 5 HIA - carcinoid tumour
17. Carcinoid tumors are of neuroendocrine origin and derived from primitive stem cells in the gut wall, especially the appendix.

BRCA1 and BRCA2 - breast and ovarian cancer.

Inflammatory bowel disease

[!TIP] A great summary!
Source

[!INFO] Differentiation of disease is vital to determine the potential effectiveness of surgery!
resection is curative in UC but disease recurs after resection in Crohn's;
Mnemonic: "Colectomy is curative"

[!INFO] NOTE! Crypt abssesses are present in both but more common in ulcerative colitis.

Peak incidence for both is between 15-30 years. But disease can occur at any age.

Research shows smoking – specifically the chemical nicotine in tobacco – seems to both guard against ulcerative colitis (UC) and help ease symptoms.

[!INFO] 'Positive features' of Ulcerative colitis not seen in Crohn's disease

• Toxic megacolon can occur.
• Marked pseudopolyps
• ? More malignant potential
• Rectal involvement is always present
• ❗primary sclerosing cholangitis (seen mostly with UC)
• more likely to develop pyoderma gangrenosum

• Apparently, ulcerative colitis is associated with thrombocytosis. #2020SBR-JUL/Q12

  • 

• In Ulcerative colitis, weight loss is a feature only of severe disease.

• Weight loss appears to be more common in Crohn's disease.

• You'd expect that to be due to malabosorption but megaloblastic anaemia is 'unusual' in crohn's disease (and UC doesn't involve the small intestine anyway) -> ?probably due to systemic effect of chronic inflammation.

• ?UC patients may be more likely to have blood in the stool.

Extraintestinal manifestations of Crohn's disease IBD

#2021SBR-NOV/Q08
Extraintestinal manifestations are common to both diseases.
Joint complications are the most common:

1. Migratory arthitis - appendicular skeleton. Parallels intestinal disease. Treatment of intestinal disease resolves arthritis.
2. Perichonlangitis - seen on ERCP or MRCP.
3. Kidney stones- seen in crohn's disease (?could be due to defective enterohepatic circulation of bile salts)
4. Bowel inflammation -> ureteric obstruction and hydronephrosis
5. Fistulas

Ileal resection can cause bile acid malabsorption -> diarrhoea.

Management options for IBD

Goal of treatment is to prevent recurrences and promote healing of existing lesions.

Crohn's disease

Induction of remission

• ❗steroids - oral or IV
  • In midly active Crohn's disease with low risk, oral budesonide is used because is has low systemic absorption.
  • IV steroids are used for severe disease. Source
• ❗Second line agent - anti TNF-alpha antibodies -> infliximab, adalimumab; best used in combination with azathioprine.
  • (can be used as steroid sparing agents)
  • They induce healing of lesions
  • Intermittent dosing leads to formation of inactivating antibodies -> regular dosing is required.
• Azathioprine, mercaptopurine and MTX can also be used.
• Exclusive enteral nutrition helps to induce remission.
• aminosalicilates are of NO benefit.

Maintenance

Except for steroids, the others can be used for maintenance.

Ulcerative colitis

Induction of remission

• Local 5 amino salicilates are the mainstay of treatment. (Mesalazine , Olsalazine, Balsazide, Sulfasalazine)
• They act topically.
• Delivered via enema (for left sided colitis) or suppository (proctitis) or oral for extensive disease.
• Mechanism of action unknown.
• Second line options for resistant disease: anti TNF-alpha inhibitors (infliximab, adalimumab) or anti integrin (vedolizumab), or tofacitinib(Oral inhibitor of JAK pathway).
• Severe colitis - IV hydrocortisone with enoxaparin to prevent thromboembolism.
  #2020SBR-JUL/Q12
  

Maintenance

#TODO

Primary sclerosing cholangitis

• Initial symptoms: obstructive jaundice, pruritus, fatigue etc.
• Progressive and chronic liver disease caused by autoimmune mediated fibrosis of intra and extrahepatic bile ducts.
• Strongly associated with IBD (mainly ulcerative colitis) -> both have ⬆levels of pANCA.
• Associated with pANCA positivity.
• Often complicated by recurrent cholangitis and cholangiocarcinoma. (20% will develop cholangiocarcinoma)
  • Also can cause osteoporosis
  • Fat soluble vitamin malabsorption
• Treatment is not curative; it's aimed at minimizing symptoms and managing complications.
• Liver transplantation is the only treatment than can alter progression. Drugs won't work.
• Affects young to middle aged males (in their 40s)
  • PSC without IBD is more likely to occur in women.
  • PSC is seen predominantly in non smokers.
  • Mmemonic: (Remember that smoking protects against ulcerative colitis! so if you smoke, you have less risk of UC and associated PSC)
• Ix: AST, ALT, GGT all elevated. Fluctuating conjugated hyperbilirubinaemia.
• pANCA positivity is a feature.
• hypergammaglobulinaemia is present.
• Best imaging modality: MRCP
• ultimately leads to cirrhocis.

Primary Biliary Cirrhosis / Primary Biliary Cholangitis

#2021GM-JUL/Q39

[!TIP] PBC - the C can stands for Cirrhocis or Cholangitis.

[!TIP] When to suspect
Suspect in a middle aged woman with pruritus who has elevated ALP and possibly other autoimmune conditions.

[!TIP] Mnemonic: Don't confuse with PSC - PBC has 'cirrhosis' in the name -> liver tissue is inolved -> interlobular bile ducts are involved.
Middle aged, itchy woman - Karens
ALP is the only abnormal investigation

MCQ Discussion:
Most often diagnosed through routine screening.
❗Usually asymptomatic. -
But Fatigue is a prominent presenting symptom. Pruritus is an early and common sign. Icterus is late signs.

• 95% of PBC occurs in women aged 40 - 50 years.

• There is destruction of small interlobular bile ducts.

• Antimitochondrial antibodies are found in all patients. M2 is specific for PBC.

  • The presence of serum antimitochondrial antibodies (AMA) is a highly specific indication of primary biliary cirrhosis (PBC).

  • Also anti GP210 - corelates with development of liver failure.

• Presentation: Asymptomatic with #hepatomegaly and raised ALP. (raised ALP is often the only abnormal investigation)

  • In Primary Biliary Cirrhosis, the level of ALP is generally greater than that of GGT. In this case, transaminases are invariably normal or only minimally elevated.Source

• Pruritus and fatigue.

• Raised cholesterol and Xanthelasma

• Associated with many autoimmune conditions.

• Also associated with RTA. - but ?rare

  • Histology: portal tract infiltrate with hepatic granulomas; changes start in zone 1.

• 

🔖Immunoglobulin / antibody classes

#2022BSQ Q49

Types of immunoglobulins and antibodies
IgG IgA IgD IgM IgE


Source

• Only IgG can pass through the placenta!
• IgA is present in breast milk as well!

🔖Insulin

#2022BSQ-OCT/Q40

Sources of insulin

Animal based : not commonly used.
Bovine insulin differs from human by 3 amino acids, porcine by 1 amino acid.

Pharmacokinetics

Regular insulin and NPH insulin are considered older insulins.
Their time to peak and duration of action don't mimic physiologic secretion.

❗(U-100) denotes the usual concentration (100 U/ml).

Regular insulin

• Duration: Short acting.
• Controls post prandial glucose rise.
• Same AA sequence as human insulin.
• Bound to Zinc.
• Hexamers must be converted to dimers and monomer before absorption -> leads to a delay in peak concentrations-> should be given 30 minutes before meals.
• Duration of action tends to exceed duration of post prandial glucose rise -> risk of hypoglycaemia.

NPH insulin

Duration: Intermediate.
Suspension of human insulin, protamine and zinc. -> delays release of insulin into blood, also longer time to peak.
Patient must eat after the morning dose is given, to avoid hypoglycaemia.

Delivery :

mix immediately before injection and given at room temperature.
NPH insulin is a cloudy solution.
Can be mixed with regular or rapid acting insulins in the syringe.
Always draw up the regular(clear) insulin first to avoid contaminating the regular insulin with isophane insulin, thereby altering its pharmacokinetics.

U-500 insulin

Not regularly used nowadays, partly because of the advent of DPP-4 inhibitors.

Insulin analogs

made by recombinant DNA technology.
Substitution of amino acids produces rapid acting and long acting analogs.

Rapid acting insulins

Lispro, aspart, glulisine (and faster aspart, lipro-aabc)
Duration: (very short) duration and rapid onset

modifications were made in the insulin molecule to prevent it from forming hexamers or polymers that slow absorption and delay action

Insulin aspart- substitution of aspartic acid for proline at position B28.

Insulin lispro is identical to human regular insulin except for a lysine and proline at positions B28 and B29.

Insulin glulisine has a lysine and glutamic acid at positions B3 and B29 respectively.

Rapid acting insulins are more convenient.
U-200 lispro and U-200 lispro-aabc, are high concentration preparations which have some niche use cases.

Basal insulin analogs

Determir

Insulin detemir – Detemir is an acylated insulin; the fatty acid side chain allows reversible albumin binding as well as concentration-dependent self-association (ie, formation of dihexamers) that results in prolongation of action.
Determir is much less potent - so it is formulated in a 4:1 ratio. (1 Unit of determir contains four times as many insulin molecules as any other preparation of insulin)
❗Can't mix with rapid acting insulins.

Glargine

Glargine is identical to human insulin except for a substitution of glycine for asparagine in position A21 and by the addition of two arginine molecules to the amino terminus.

After subcutaneous administration, glargine precipitates in the tissue, forming hexamers, which delays absorption and prolongs duration of action.

Glargine, which is in an acidic solution, cannot be mixed with rapid-acting insulins, as the kinetics of both the glargine and rapid-acting insulin will be altered

Glargine has less nocturnal hypoglycemia than NPH insulin

Duration of action : 24 hours but some may need twice daily dosing as half life is 12 hours. Unlike glargine, determir has a small peak in it's concentration profile.

Higher concentration preparations of glargine (U-300) have an even flatter concentration curve with lower hypoglycaemic effect.

Degludec

form multimers from which monomers are release-> even longer duration of action.
Can mix with rapid acting insulins.

[!TIP] Degludec - the only long acting insulin that can be mixed with rapid acting insuline Mnemonic: Glue - glue it up.

Determinants of insulin efficacy

• Site of injection - Limbs are faster than abdomen. (muscle-> increased blood flow)

  • 

  NPH insulin - leg or buttock preferred for moderate rate of absorption.
  Pre meal regular insulin - abdominal wall preferred for rapid absorption.

The absorption of the long-acting basal insulin analogs, glargine and degludec, do not appear to be significantly influenced by injection site

• Technique
  • Too shallow: intradermal injection that is not well absorbed.
  • Too deep: intramuscular -> rapid absorption
  • 4mm neele - can give perpendicular injection
  • 6mm needle - give at 45 degrees.
  • Rotate sites to avoid lipohypertrophy.
  • Injection through clothes won't cause dlivery problems but it means that skin cannot be inspected before injection -> not recommended.
• Size of the depot
  • Larger depot size - less overall absorption and more variability in absorption.
• subcutaneous blood flow
  • reduced by smoking
  • Increased by exercise and hot baths.
  • Variations not as significant with long acting insulins.

Insulin administration in the elderly

#2020BSQ-JUL/Q25
This Source and other articles in general seem to indicate that basal bolus regimes are too rigorous to follow for elderly people.
Morning basal insulin regimens may be recommended. Usually, for fasting hyperglycaemia, nocturnal basal dose is given.

Types of hypersensitivity

#2022BSQ Q48
#2022BSQ-MAY Q46

Hypersensitivity reactions refer to undesirable responses produced by the normal immune system - Source

[!INFO] Mnemonic
Type III - 3rd letter in alphabet - C for immune complexes.
[[Toxicology#Serum sickness]]

• Type III: immune complex mediated.
  • Arthus reaction is a type of Type III reaction
  • The Arthus reaction involves the in situ formation of antigen antibody complexes.
  • Manifests as a local vasculitis (at the bite or injection site) due to deposition of of IgG based immune complexes in dermal tissue.
  • 
  • 

Type 5 hypersensitivity

Is when the produced antibodies have the property of stimulating receptors on cells. Best example is Grave's disease.
Source

[!TIP] Hypersensitivity Vs Autoimmune disease
Hypersensitivity is an abnormal immune response to a harmless stimulus. When the 'stimulus' is a self antigen, we call it autoimmunity.

Autoimmune diseases can be classified in the same way as hypersensitivity conditions. but IgE is not involved in autoimmunity.
so in the table[[2022 November SBR]] below, there is no "type I" in the autoimmune categories

🔖Autoimmune diseases examples

Autoimmune diseases caused by antigens against cell surface receptors: [[moreAutoimmuneDiseases.png]]

Infectious diarrhoea

#2022BSQ Q54

Summary table of traveller's diarrhoea

[!TIP] The types of E coli - "HIT"
enterohaemorrhagic (EHEC) (aka STEC - shiga toxin producing E coli)
enteroinvasive (EIEC)
enterotoxigenic (ETEC)
The first two cause bloody diarrhoea.

But there are actually 5 types.

1. ETEC causes watery diarrhea in resource-limited settings and is commonly found in food and water in areas without adequate sanitation
2. EPEC (enteropathogenic) was the first E. coli pathotype identified as a causative agent of watery diarrhea primarily in infants and young children in resource-limited settings
3. EAEC (enteroaggregative) is a causative organism of acute and chronic watery diarrhea in resource-limited and resource-rich regions
4. EHEC/STEC produces Shiga-toxin and includes serotypes O157:H7, as well as others
5. EIEC-induced diarrheal illness is uncommon due

• Source

Diarrhoea in resource rich settings

• can be studied under inflammatory diarrhoeal causes and watery diarrhoeal causes.
  See mnemonics below:

[!INFO] A Great table!
[[diarrhoeaInResourceRichSettings.png]] <- A great table!

[!TIP] Watery diarrhoea
"Noninflammatory diarrhea is caused by the action of enterotoxins on the secretory mechanisms of the mucosa of the small intestine, without invasion" - Medscape.

Same day:

1. Norovirus (mnemonic : N for 'naught' for day zero) ("winter vomiting bug" - also causes vomiting)
2. clostridium perfringens
3. possibly listeria (pregnancy, immunosuppression, extremes of age)

Next day:

1. E coli - enterotoxigenic
2. most other viruses - (1-3 days) diarrhoea in children, immunocompromised adults
3. (including Rotavirus)

Same week

1. [[Misc infectious diseases#Cyclospora cayatensis infection|Cyclospora infection]]

Weeks later

1. Giardia 1 to 2 weeks later - day care, swimming pools, travel / camping.
2. Cryptosporidium 2-28 days (upto 1 month after) - Associated with day care centers, swimming pools. (common in HIV patients)
3. see [[HIV-AIDS#Selected aids defining illnesses]]

^5eaea3

[!TIP] Mnemonics: inflammatory diarrhoea
Fever, mucoid or bloody stools show infective diarrhoea:
"Can't Assume Everyone's Your Very Special Sidekick"

Let's break it down:

1. "Can't" - Campylobacter
2. "Assume" -[[2023-SEMPaper#Amoebiasis|Amoebiasis]]
3. "Everyone's" - E. coli
4. "Your" - Yersinia
5. "Very" - Vibrio parahaemolyticus
6. "Special" - Salmonella
7. "Sidekick" - Shigella

Most of these have P-incu of 1-3 days.
But, entamoeba - much longer- 1 to 3 weeks, yersinia - slightly longer- 4-6 days, E-coli 1-8 days.

Complications of dysentery include [[General medicine 3#Guillain barre|GBS]], [[2022-SBR-MAY#Reactive arthritis]]

management of campylobacter diarrhoea

• Usually self limited
• Severe cases may need antibiotics: clarithromycin (macrolide)

Giardiasis

[!INFO] Giardiasis is one of the most common intestinal infections worldwide in both developed and developing countries

• Giardia lamblia - 'old mans face appearance', protozoan.
• Causes water diarrhoea after a few weeks -> cyst is the infective state; cysts produce trophozoites which attach in the small intestine and colon.
• 
• Cyst is the infective stage. (Cysts are immediately infectious upon excretion, they can survive chlorinated water)
• Cyst are ingested via contaminated water or food (like salads). Faeco-oral person to person transmission can occurs (eg. Child care centers)
• 
• Trophozoite attaches to proximal small intestine, sometimes causing villous atrophy.
  • Mmnemonic: "old man is bald" (old mans face -> "bald" intestinal wall)
• Abdominal pain, watery diarrhea, weight loss.
• can cause malabsorption in paediatric population.
• Severe infection can invade the mucosa in severe infection but usually there is no invasion.
• Can rarely invade pancreas and bile ducts.
• Diagnosis : stool microscopy, string test, also PCR on stools samples.
• High risk: Immunocompromised, infants
• Treatment: tinidazol, metronidazole is second line due to concern of side effects. Achieves parasite clearance within 1 week.

Diarrhoea in resource poor settings

Epidemic diarrhoea

Main two pathogens of epidemic diarrhoea

1. Cholera (secretory rice water diarrhoea) [[Misc infectious diseases#Cholera]]
2. Shigella dysenteriae (bloody diarrhoea) - SD1 serotype. (inflammatory diarrhoea - blood + mucous)

Non epidemic diarrhoea

Commonest causes of non epidemic watery diarrhoea - E. coli.

[!TIP] mnemonic
Acute bloody diarrhoea
$$
{C^1S^2E^3}
$$

Commonest cause of non epidemic bloody diarrhoea - shigella flexneri (not dysenteriae)

• other causes of acute bloody diarrhoea
  • Campylobacter
  • Enteroinvasive E coli
  • Enterhemorrhagic E coli
  • Entamoeba histolytica
  • [[Misc infectious diseases#Schistosoma|Schistosoma mansoni]]

Diarrhoea due to preformed toxins

#2021BSQ-NOV/Q37

Symptoms suggesting diarhoeal illness caused by preformed toxins:

• Absolutely Rapid onset of symptoms : within hours.
  • Bacteria which start to form toxin after ingestion take time to produce symptoms. (usually> 24 hours)
• Vomiting predominates in the clinical picture.
• Pathogens causing diarrhoea this way are
  • Staphylococcus aureas - Toxin is produced on food at room temperature; food doesn't taste or smell odd. Onset as rapid as Source 30 minutes!
  • and Bacillus cereus - can be symptomatic within 6 hours!
    • classically occurs after eating preserved rice.

Enterobiasis

• Pin worm.
• Humans are considered the only host for E. vermicularis
• Infection is commonest in children and institutionalised people.
• Treatment is easy; reinfection is also easy.
• Commonest symptom: itching in the perianal area, possible with excoriation and secondary bacterial infection.
• Perianal itching / scratching contributes to faeco-oral transmission of the parasite.
• Infection of the female genital tract can occur. Can cause abdominal pain mimicking appendicitis.
• Treatment: Albendazole, mebendazole

🔖Strongyloidosis

#2020BSQ-NOV/Q50

• Strongyloides stercoralis : thread worm
• First discovered in french troops returning from vietnam in the 19th century who developed chronic diarrhoea.
• Infective stage : Filariform larva: -> penetrates intact skin.
• Shows autoinfection.

[!INFO] How to understand the life cycle;
parasite has a free living cycle and parasitic cycle.
So adult worms can be found in the environment and the intestinal lumen of hosts.
Eggs can be deposited a) In the host intestine and b) in the environment.
Eggs always produce rhabditiform larvae.
Eggs -> rhabditiform larvae -> filariform larvae. (Infective stage) (autoinfection or otherwise).
If excreted with stool, rahbditiform larvae can go on to develop into adult sexual stages which produce more eggs in the free living cycle.

Female Adult worm (who live embedded in the submucosa of the small intestine) lays eggs.

It has been thought that the L3 larvae migrate via the bloodstream and lymphatics to the lungs, where they are eventually coughed up and swallowed. However, L3 larvae appear capable of migrating to the intestine via alternate routes (e.g. through abdominal viscera or connective tissue)

Symptoms:

Respiratory : Dry cough - about 1 week after infection
Abdominal pain, bloating, intermittent constipation and diarrhoea - about 3 weeks or later after infeciton (due to infection of the small intestine)
Skin: Itchy rash at site of entry; recurrent red rash along thighs and buttocks. - Larva currens (pathognomonic of Strongyloidiasis).
Disseminated life threatening infection can occur in immunosuppressed people.
Eosinophilia(+).
Can cause [[2021-SBR-November#Loffler syndrome / Loeffler syndrome | Loeffler syndrome]]

Management:

Ivermectin has been shown to be superior to albendazole.

Ivermectin: binds selectively and with high affinity to glutamate-gated chloride ion channels in invertebrate muscle and nerve cells of microfilaria.

Albendazole and other similar drugs inhibit the beta tubulin of worms (intracellular cytoplasmic structural protein) -> immobilization and death.

🔖Echinococcosis

#2020BSQ-NOV/Q50
? Dog tape worm
A 2-7mm long small tape form whose definitive host is the dog.
Intermediate host is animals like sheep.
Sheep tissues have cysts which are infective when ingested by a dog.
The adult forms in the dog then shed eggs with faeces which are usually ingested by the sheep, but can also be ingested by humans.
One ingested, the eggs hatch the the larvae penetrate the intestinal wall and take up residence in the tissues.
In the tissues, they from hydatid cysts.
The cysts usually grow for many years and are asymptomatic until they cause symptoms due to pressure effects.
However, if a cyst ruptures, it can cause analphylaxis, or a milder fever, and dissemination of the parasites within.
Treatment: Surgery or less invasive procedures like PAIR (percutaneous aspiration, injection of chemicals and reaspiration).

[!TIP] Sheepdog

Trichinellosis

#2020BSQ-NOV/Q50


Image of skeletal muscle encysted and liberated trichinella parasite.

• Trichinella is acquired by ❗eating undercooked meat which contains the cysts.
• ?one species is Trichinella spiralis (photos above looks like a spiral)
• They initially colonize the GI tract -> gastrointestinal symptoms.
• Excystation occurs after ❗passage through gastric acid. Excysted larvae develop into adults which produce larvae which migrate through the intestinal wall and encyst in host skeletal muscle about 1 week later after infection.
• Clinical features are somewhat distinctive: periporbital oedema, facial oedema, ❗conjunctivitis, fever, splinter haemorrhage, rashes, and peripheral eosinophilia.
• Occasional life threatening manifestations are CNS involvement, myocarditis, and pneumonitis.

Treatment:
Albendazole and mebendazole for about 14 and 10 days respectively. Treatment should be started within first few days of infection, or else, larvae will migrate into skeletal muscle and treatment will not completely eliminate the infection.

Trichiuris

Trichiuris trichiura - the human whipworm

[!INFO] Delayed action "haal atey"

• Maginified endoscopic images of a trichiuris parasite in the colon. Source
• The adult is about 4 cm in length.
• The adult worms embed into the mucosa with the anterior part and live in the caecum and ascending colon, shedding thousands of eggs per day. Their lifespan is about 1 year.
• Unembryonated eggs enter the soil with faeces and become infective only after about 15 to 30 days.
• Embryonated eggs are the infective stage and are transmitted by the faeco-oral route.
  Symptoms
• Commonly asymptomatic
• Heavy infestations in children can cause abdominal pain, diarrhoea and rectal prolapse, impaired growth, anaemia, impaired cognitive develoment.
• Heavy infections can cause stool with mucous and blood. (?probably due to the mucosal attachment of the worms) and rectal prolapse.

Diagnosis:

• By microscopic identification of worm eggs in faeces.

Treatment:

• Albendazole, mebendazole or ivermectin for 3 days. Effectively treated.

Ascariasis

• Soil tranmitted helminths (STHs)
• Aka roundworm
• Transmission is faeco oral by ingestion of fertilized eggs. (unfertilized eggs are not infective).
• Live cycle involves migration through intestine to portal vein to systemic circulation to lung from where they migrate up the trachea -> pharynx and are then swallowed to enter the GIT.
  • One cause of [[2021-SBR-November#Loffler syndrome / Loeffler syndrome|Loeffler syndrome]]
• Adult worms live in the small intestine.
• Adult worms are about 20cm long!
• Symptoms: Usually asymptomatic but very high burden can cause obstruction and perforation.
  • Biliary occlusion
  • Appendicitis
  • Nasopharyngeal expulsion

Treatment:

• Albendazole, mebendazole

Skull base fracture

#2022BSQ Q51
Skull base fracture and associated injuries; Source
NCBI article <- good link
Cranial nerve injuries: Page 1079 of Moore's clinical anatomy.

Posterior fossa signs: battle signs, haemotympanum, loss of gag reflex and accessory nerve palsy.

Sjogren syndrome

#2022GM Q14
#2021GM-JUL/Q17

[!TIP] Mnemonic
SR4 : Sjogrens => RoLa+ / RF+ / RTA / Raynaud

Pathogenesis: Autoimmune disease affecting exocrine glands.

In most cases, Sjogren syndrome is only 'irritating' and not dangerous.

Can occur as a primary disorder or secondary to another rheumatic disease.

Symptoms are classified mainly as

1. Exocrine gland symptoms
   1. Predominant symptoms of Sjogren's syndrome are
      1. oral dryness (affects salivary glands)
      2. and dry eyes. - assessed by Schirmer test < 5mm/min. (filter paper used to assess tear production)
2. Extra glandular symptoms
   1. Skin :
      1. Xerosis (dryness)
      2. Raynaud's phenomenon
      3. Cutaneous vasculitis: Palpable purpura is the commonest manifestation.
   2. Muskuloskelatal: Arthralgria, myopathy, fibromyalgia.
   3. Associated with autoimmune thyroiditis.
   4. Lungs - interstitial lung disease; upper and small airway involvement; Patients have ❗cough and dyspnoea.
   5. Peripheral neuropathy
   6. Depression / mood changes/ mild cognitive impairment (maybe due to poor sleep)
   7. Mild anaemia and leukopenia
   8. Other autoimmine diseases
      1. Myasthenia gravis
      2. Autoimmune hepatitis/ pancreatitis.
      3. Autoimmune thyroiditis
   9. Increased incidence of Non Hogdkins B lymphoma.
   10. Can cause renal involvement - hypokalemia is common secondary to distal renal tubular acidosis [[2021-SBR-November#Renal tubular acidosis]] with K+ wasting.
   11. Rare complication of Sjogren syndrome during pregnancy : congenital heart block.
   12. ?Dysphagia with abnormal oesophageal motility.

Spectrum of disease:

Mild disease : just dry eyes and mouth; Requires diagnostic criteria to be fullfilled to diagnose SjD.

Severe disease:
A severely affected patient may have florid salivary gland enlargement, adenopathy, antibodies to the Ro/SSA and La/SSB antigens, cryoglobulinemia, hypocomplementemia, a propensity to develop non-Hodgkin lymphoma, and other extraglandular disease manifestations.

90% are positive for Rheumatoid factor: Kumar and Clark

Epidemiology: Most Commonly occurs in women aged 50-60 years old.

Associated conditions

Keratoconjuntivis sicca - term for the occular manifestations of Sjogrens.
Mikulicz syndrome: Parotid and lacrimal gland enlargement;

• Characterized by sudden onset dry mouth leading to difficulty in swallowing.
• Hard painless swellings of the salivary glands.
• Symptoms are very similar to Sjogren's syndrome.
• Sjogren's disease is one possible cause of this.

Diagnostic criteria:

Biopsy showing focal lymphocytic infitrate of labial salivary glands. Termed Focal lymphocytic sialadenitis.

Objective test: Focal lymphocytic sialadenitis score >= 1;

Anti Ro/SSA and anti La / SSB positivity suggests Sojgren's disease.

Background of systemic autoimmune disease. -
The most common associations are SLE and Rheumatoid arthritis.

🔖Pathogenesis of ascites in Cirrhocis

#2020SBR-JUL/Q18

This flow chart shows the mechanism of activation of various vasoactive systems in cirrhosis.

Several haemodyanic and vascular changes occur which contribute to the formation of cirrhocis.

Vascular:

• Decreased peripheral resistance (and reduced arterial pressure)
  • (most apparent in the splanchnic circulation)
• Increased circulatory volume
• Increased cardiac output (and tachycardia)
• Increased portal blood flow
• I.e Hyperdynamic circulation is present.
  but, with
• Decreased renal perfusion (kidneys compensate by increasing their production of prostacyclin - a vasodilator. ❗This effect is lost in patients with hepatorenal syndrome and can be inhibited iatrogenically by ❗NSAIDS -> both causing a ==disastrous== fall in renal plasma flow!)

Multiple mediators have been studied as sources of the systemic vasolidation but the most important one seems to be increased NO synthesis.

inhibition of synthesis of NO in rats restores normal arterial pressure.

? cause for increased NO
Portal hypertension -> increased portosystemic shunting -> decreased hepatic clearance of bacterial toxins / DNA absorbed from GI tract.

mediated by vascular changes:
Splanchnic vasodilation
Renal artery vasoconstriction
(and also pulmonary vasodilation)

Ascites: The pathological accumulation of fluid in the peritoneum.
Development of portal hypertension is the first step and is essential for the formation of ascites in cirrhocis.

Older theories of ascities formation : undefill theory and overflow theory. Modern arterial vasodilation hypothesis fits better with data.

Arterial vasodilation theory of ascites formation

A portal pressure >12 mmHg appears to be required for fluid retention
Portal hypertension is not simply due to mechanical obstruction of the portal system. It occurs due to increased flow from the splanchnic arteries.

See hypothesis-highlights on UpToDate

SAAG

#2022GM Q32
Serum 'to' Ascites Albumin gradient

SAAG > 11g/L - low protein in ascitic fluid => Suggest portal hypertension as cause; (i.e transudate)
SAAG < 11g/L - high protein in ascitic fluid (or low serum protein) => Exudate (?malignancy)

❗Low ascitic fluid protein may increase the risk of SBP as there are no opsonins in the fluid to combat infection.

Liver transplantation

Indications for liver transplantation

1. Acute liver failure of any cause
2. Chronic hepatic failure with Childs grade > C or MELD > 20;
   1. hepatopulmonary syndrome can be reversed by hepatic transplantation.
3. Primary biliary cholangitis
4. Chronic hepatitis B is HBV DNA negative or falling; recurrence of infection is prevented by HBIG and nucleoside analogues.
5. Autoimmune hepatitis
6. Alcoholic
7. Metabolic disorders - haemochromatosis, Wilsons, Alaph a antitrypsin deficiency
8. NASH cirrhocis

Management of Ascites

#2020SBR-JUL/Q18

• Treatment is based on treating the underlying hepatic disease and the salt and water retention.
• while avoiding intravascualr depletion.

Measures to reduce ascites:

• Encourage alcohol abstinence.
• Dietary sodium restriction.
• Avoid certain antihypertensives (which may seem beneficial due to their RAAS blockages effect) :
  • In patients with cirrhosis, lower arterial pressures corelate with higher mortality. Therefore, medications which may reduce ascites but also are antihypertensives should be avoided in those with progressive cirhosis and declining blood pressure.
    • Avoid ACEi / ARB , beta blockers in these patients.
    • NSAIDS can reduce sodium excretion (through prostaglandin inhibition) so avoid in ascites.
• Diuretics: Spironolactone in combination with frusemide in the ratio 100 mg and 40 mg. (UpToDate)
  • Basis of diuretic therapy: Source
    • Spironolactone counteracts hyperaldosteronism seen in cirrhosis.
    • Frusemide alone is inferior to spironolactone alone.
    • Combination therapy provides faster ascites mobilization.
  • Target ascites reduction of 300-500 ml/day (max) if patient has no oedema.
  • If patient has oedema, higher rates can be achieved. (?about 1kg/Day?) (max of 2kg/Day)

  • In general, the goal of diuretic treatment of ascites should be to achieve a weight loss of 300-500 g/d in patients without edema and 800-1000 g - MedScape

Bronchiectasis

#2022GM Q21
#2017GM-OCT/Q10

Review of airway histology

Respiratory epithelium - ciliated pseudostratified columnar epithelium.

Note the presence of smooth muscle and it's decreasing thickness as the airways become smaller.

Bronchioles - intralobular airways < 1mm in diameter arising roughly after the 10th generation of branching.

Epidemiology

Commoner in women.
Increases with age; marked increase after 60 years.

Pathology

Bronchiectasis is the permanent dilation of bronchi and
bronchioles caused by destruction of the muscle and the
supporting elastic tissue, resulting from or associated with
chronic necrotizing infections. It is not a primary disease
but rather secondary to persisting infection or obstruction
caused by a variety of conditions

Once patients develop bronchiectasis, most commonly isolated organisms are haemophillus and pseudomonas and streptococcus pneumoniae.

Obstructive impairment (ie, reduced or normal FVC, low FEV1, and low FEV1/FVC) is the most frequent finding on spirometry. ;
$$
\LARGE{Obstruction = ↓\frac{FEV_{1}}{FVC}}
$$

See [[Lung function tests#Obstructive vs. restrictive diseases]]

Morphology

• Usually affects bilateral lower lobes.
• Permanent dilation -> small airways are traceable almost upto the pleura. (in normal lungs, they stop about 2 cm short of the pleura)
• Chronic inflammatory exudate is seen.
• Extensive desquamation of epithelium causing ulceration.
• Healing is usually by fibrosis.
• Abscesses can form as complications.

Diagnosis:

Clinical and CT:
CT features that are reliable signs of bronchiectasis:

• Airway-to-arterial ratio ≥1.5 (internal airway lumen diameter/adjacent pulmonary artery diameter)
• Lack of tapering of bronchi (tram track appearance)
• Airway visibility within 1 cm of a costal pleural surface or touching the mediastinal pleura

Causes of bronchiectasis and basis of disease

Common causes

Obstruction - tumour, lymph nodes, aspiration etc. <- impaired drainage
Inherited disorders -
Cystic fibrosis #autosomal-Recessive <- impaired clearance of mucous
Kartagener syndrome <- Ciliary impairement
Autosomal recessive #autosomal-Recessive
Situs inversus, chronic sinusitis, and bronchiectasis; Underlying pathology is primary ciliary diskinesia. Kartagener Xn is a subset of primary ciliary diskinesia (in which patients may not have situs inversus).
Screening test -> patients have low levels of nasal nitric oxide.

Immunoglobulin deficiencies <- recurrent infection
Necrotizing of suppurative pneumonia - staph aureus or klebsiella <- scarring and impaired clearance; ?exagerrated neutrophil response

Cystic fibrosis

• #autosomal-Recessive ; requires two mutated copies of the CFTR gene involved in chloride and bicarbonate transport.
• patients have thick secretions in lungs, GI tract, pancreas and reproductive tract.
• Features: Chronic respiratory tract infections, including pseudomonas.
• Males have obstructive azoospermia due to bilateral absence of vas deferens, allergic bronchopulmonary aspergillosis, clubbing, pancreatic insufficiency, hypochloremic alkalosis, rectal prolapse and others.
• Sperms express CFTR and spermatogenesis may be reduced.
• Diagnosis: elevated sweat chloride, abnormal nasal potential difference.

Other causes

Young syndrome - similar to CF but no evidence of CF; rare diagnosis nowadays.
Associated with two rheumatic disorders - Sjogren syndrome and Rheumamtoid arthritis.
[[General Medicine 1#Allergic bronchopulmonary aspergillosis|Allergic bronchopulmonary aspergillosis]] - ? central bronchiectasis

Management

Antibiotics for exacerbations
Control of acute bleeding with bronchoscopic local therapy or bronchial artery embolization.
Refractory disease: surgical therapy - ? resection

🔖Immunodeficiency syndromes

• Primary immunodeficiencies arise from inborn defects. They usually present in childhood.
  • Common variable immunodeficiency is a notable exception to this.
• Secondary immunodeficiency is far more common (?in adult populations)
  • Diabetes mellitus
  • Human immunodeficiency virus (HIV) infection
  • Cirrhosis
  • Nephrotic syndrome
  • Other protein-losing states, such as enteropathies, severe exudative skin disease including burn injury, and peritoneal dialysis
  • Malnutrition
  • Hemoglobinopathy
  • Inflammatory bowel disease or rheumatoid arthritis receiving immunosuppressive therapies (particularly tumor necrosis factor [TNF] inhibitors)
  • Neurologic disease
  • Autoimmune disease
  • Splenectomy
  • Malignancy
  • Radiation therapy
  • Immunosuppressive agents, such as glucocorticoids and others
  • Immunomodulatory agents, such as rituximab, etanercept, and others

Typical presentations and associated defects in the immune system

#2022BSQ-MAY/Q49

Skin infections, in isolation, are not usually indicative of an underlying primary immunodeficiency.
Chronic mucocutaneous candidiasis - ussually begins in childhood; associated with several immunodeficiency states; usually doesn't show systemic infection with the fungus.
Recurrent herpevirus infection / reactivation -> These individuals should be evaluated for underlying T or natural killer (NK) cell dysfunction. See -> [[2021 Basic Sciences July#Natural killer cells]]
 ***
 However, recurrent respiratory tract infections in combination with more serious infections are a classic presentation of antibody deficiencies.
 ***
~~>  
 - Isolated urinary tract infections are more suggestive of anatomic defect than immunodeficiency.
 - Relapsing, recurrent, and/or progressive enterocolitis due to common enteropathogens, such as Giardia, enteroviruses, cytomegalovirus, and campylobacter, are associated with underlying hypogammaglobulinemia and/or T cell immunodeficiency.
 
 - Recurrent Neisseria meningitidis meningitis -> Deficiency of one or more of the terminal complement components (C5, C6, C7, C8, C9) . Low complement levels may be due to either congenital complement deficiency or acquired diseases, such as systemic lupus erythematosus.
 - Immunoglobulin deficiency disorders or impaired reticuloendothelial function resulting from splenectomy or hemoglobinopathy are associated with an increased risk of bacteremia and meningitis due to encapsulated pathogens.
 - Marked elevation of serum IgE with multisystem infections -> Job syndrome
~~

Immunoglobulin / antibody deficiencies

Usually due to defects in B lymphocytes -> not enough antibodies produced.

Recurrent sinopulmonary infections and persistence of gut pathogens.
Leads to bronchiectasis and chronic diarrhoea with malabsorption.

Common variable immunodeficiency

[!INFO] Commonest significant antibody deficiency affecting children and adults.

Diagnosed at: 20 and 45 years of age.

? etiology - few are inherited. Pattern may by #autosomalDominant with low penetrance or #autosomal-Recessive - UpToDate

There is

• B cells are present but they don't produce antibodies (i.e are ?nonfunctional?)
  • B cell numbers are normal but there are low levels of isotype switched B memory cells and plasma cells.
• Low levels of all immunoglobulin classes
• Frequent bacterial infections.
• Lymphoma is a common cause of death in these patients.

Complications:

• Recurrent infections - sinopulmonary (with encapsulated Streptococcus pneumoniae and Haemophilus influenzae and others) -> can lead to bronchiectasis.
• Autoimmune disorders - RA, vitiligo, haemolytic anaemia.
• Lymphoma

Chronic giardia infections with malabsorption can occur.

Treatment is IVIG.

Selective IgA deficiency

Commonest primary immune deficiency.
Individuals are usually asymptomatic. -> treatment is only antibiotics as needed.
Can present with recurrent mucosal pyogenic infections.

Agammaglobulinaemia

#2021BSQ-JUL/Q24
Also called hypogammaglobulinaemia.

Mutation of the BTK gene impairs B cell maturation -> causes low or absent mature B cells -> severe hypogammaglobulinaemia.
Commonest inheritance: #x-linked-recessive with mothers being carriers. #autosomal-Recessive inheritance is seen in ? 50%. - confirm

Manifestation: recurrent sinopulmonary infections.(From 6 to 12 months of age, otitis media, sinusitis, bronchitis, and pneumonia).
Common pathogens: Encapsulated pyogenic bacteria Haemophillus influenzae and strep pneumoniae.

Treatment: repeated IVIG transfusions or stem cell transplant.

Complement deficiency

[[2022-November#Complement system overview]]
Impaired alternative pathways -> non specific impairement -> bacterial infections.

Impaired classical pathway -> increased infection and increased immune complex deposition -> SLE, vasculitis, glomerulonephritis etc.

MAC -> neisseria infections.

Severe combined immunodeficiency - SCID

#2022BSQ-MAY/Q49

• Commonest form is impaired #x-linked-recessive .
• Defect is in IL-2 receptor.
  • IL-2 is a cytokine which causes proliferation of T lymphocytes specific to a particular antigen. (Figure 4-4 Robbins)
• T and NK cells are lacking in the blood.
• Presentation is similar to pure T lymphocyte deficiency:
• That is, infections with fungi, protozoa, intracellular organisms.

• persistent and recurrent diarrhoea, otitis media, thrush, and respiratory infections

• Treated with Stem Cell transplant.
• Presents before 3 months of age; without treatment babies die before 2 years of age.

Immune response to fungi

[[ImmuneResponsesTofungalpathogens.pdf]]
Not as well understood as bacteria and viruses.
Pattern recognition receptors (PRR) on antigen presenting cells are triggered by fungal cell components.
This causes intracellular signalling of the APC which promotes phagocytosis and stimulates killing mechanisms.
The adaptive immunity to fungi is mediated by CD4+ Th1 cells with produce interferron gamma and CD4+ Th17 cells which produce IL-17. They drive killing by innate effector cells like marcophages and neutrophils.

So overall,

1. neutrophil defects cause systemic candiasis
2. T cell defects cause mucocutaneous candidiasis.

🔖Neutrophil defects


[!INFO] presentation
> Is with recurrent and severe bacterial (Staphylococcus, pseudomonas, salmonella, Nocardia) and fungal (candida, Aspergillus) infections, most commonly of the respiratory tract and skin.

#2020BSQ-JUL/Q29

1. [[2022 May Basic Sciences#Chronic granulomatous disease|Chronic Granulomatous disease]] <- a defect in neutrophil killing.
2. Leukocyte adhesion deficiency -> a defect in 'firm' adhesion of leukocytes to vessel walls caused by defect in integrins. #autosomal-Recessive
   • Presents in early life with delayed umbilical cord separation, failure to lose primary dentition, severe gingivitis. There is neutrophilia but the cells cannot reach sites of infection. Recurrent infections in the first decade of life. Treatment is stem cell transplant.
3. Hyper IgE syndrome - Job's syndrome
   • #autosomalDominant
   • abnormal T cell function, increased IgE production and intermittent defects in neutrophil chemotaxis.
   • Dermatitis, boils, pneumonia
4. Schwachman-Diamond syndrome ^226faf
   • Mild neutropenia + defect in neutrophil migration.
   • Resembles cystic fibrosis clinically with exocrine pancreatic failure + pyogenic infections.
5. Chediak-Higashi syndrome
   • Defective phagolysosome fusion. (large lysosome vesicles are seen within the neutrophils)
   • Recurrent infections, anaemia, hepatomegaly.
   • One cause of primary haemophagocytic lymphohistiocytosis.

🔖Acquired neutrophil defects / neutropenia

• Hypersplenism
• Immunomodulatory drugs: colchicine, MTX
• Diabetes:
  • In diabetes, there is a failure in the neutrophil functions, including migration, ROS production, phagocytosis, and bacterial killing. Source

🔖OPSI - overwhelming post splenectomy infection

Splenectomy leaves the patient vulnerable to infection by capsulated organisms.

1. Streptococcus pneumoniae
2. Haemophillus influenzae
3. Neisseria meningititis

[!TIP] Mnemonic: Capsulated organisms : Have No Sex.

More than half of those with OPSI die.

Why specifically encapsulated organisms?

Encapsulated organisms are resistant to phagocytosis without opsonization.
❗The spleen is a major site of early IgM production.

IgM memory B cells produce IgM to promote the clearance of polysaccharide-encapsulated bacteria.

Although the total B lymphocytes remain intact, a significant fall in the levels of memory B cells and switched B cell proportions are usually encountered 150 days post-splenectomy. This acts as a particular predisposition to infections caused by polysaccharide-encapsulated bacteria and is responsible for a diminished immunological response to polysaccharide vaccines
Source

However, even after opsonization, the bacteria must be phagocytosed. Splenic macrophages are a major contributor to this phagocytosis.
So in asplenia, there is impaired IgM production and thus opsonization and also impaired phagocytosis.

[!INFO] primary Vs. secondary immune response:
Source

Amyloidosis

#2019BSQ-OCT/43
"Amyloid" was meant to describe the starch like properties of the substance. Initially described as "waxy" and "lardaceous".

Normally soluble proteins are deposited extracellularly as beta pleted fibrils.

Subtypes of amyloidosis

There are 18 different types of systemic and 22 localized forms of amyloidosis

The four most common causes of systemic amyloid deposition are

1. AL amyloidosis
2. ATTRwt - wild type transthyretin amyloidosis
3. Hereditary (familial) amyloidosis
4. AA amyloidosis (caused by serum amyloid A protein)
5. And Dialysis associated amyloidosis
   1. Dialysis-related amyloidosis (DRA) is a disabling disease characterized by accumulation and tissue deposition of amyloid fibrils consisting of beta2-microglobulin (beta2-m) in the bone, periarticular structures, and viscera of patients with end-stage kidney disease. Beta2-m is a component of the major histocompatibility complex that is present on cell surfaces and is normally cleared by glomerular filtration

[!INFO] AL Vs AA : importance of differentiating
AL amyloidosis must be differentiated from other forms of amyloidosis (eg, AA amyloidosis, ATTRmt amyloidosis, and ATTRwt amyloidosis) since the latter are non-neoplastic and will not benefit from chemotherapy.

Other forms of amyloidosis:

• Heritable amyloidosis types
• Organ specific amyloidosis
• Dialysis related amyloidosis

Diagnosis

Histological : Fat pad biopsy (less risk of bleeding)
Organ biopsy is needed if a specific organ is involved.

When Congo red stains binds to amyloid protein, it produces apple green birefringence.

Looks similar to DM nephropathy but the staining characteristics are different (DM nephropathy is PAS and silver stain positive)

Cutaneous manifestations of amyloidosis

• purpura, petechiae, and ecchymoses following minor trauma ("pinch purpura")
• Appearance of periorbital purpura following a Valsalva maneuver or dependent positioning of the head.(Racoon eyes)
• Macroglossia (picture 16), waxy papules and plaques, enlarged shoulder pads, bullous lesions, and sclerodermatous changes in the skin may also be seen. (UpToDate)

AL amyloidosis

[!INFO] MGUS to myeloma

• All patients with active myeloma once had MGUS but
• Only 20% of patients with MGUS actually progress to active myeloma.
• The risk of a patient's progression from MGUS to active myeloma is only 1% per year. Source

AL amyloidosis is Associated with plasma cell dyscrasia (multiple myeloma, waldenstrom macroglobulinemia)

📑Symptoms and signs

There is multisystem amyloid deposition

• Fatigue, non intentional weight loss

• 📑Heavy proteinuria (70%) - nephrotic syndrome

• 📑oedema

• #hepatosplenomegaly (hepatomegaly +/- splenomegaly seen in 70%)

• Cardiomyopathy and heart failure (60%) - thickening of interventricular septum is present / 📑MI due to accumulation of amyloid in coronaries.

  • Cardiomyopathy is common in AL and ATTR but 📑rare in AA amyloidosis

• Neuropathies - carpal tunnel, mixed sensory and motor peripheral neuropathy is a prominent feature in AL amyloidosis. (Symptoms of numbness, paresthesia, and pain are frequent)

• 📑Amyloid infiltration of muscles - macroglossia with scalloping and shoulder pad sign. (also enlarged deltoids)

• Skin - purpura (raccoon eyes with valsalva maneuver is specific), waxy skin, easy bruising.

• 📑Coagulopathy - possibly due to factor X binding of coagulation factors to amyloid.

• 📑GI involvement: gastroparesis, constipation, bacterial overgrowth, malabsorption, and intestinal pseudo-obstruction resulting from *dysmotility

  Criteria for organ involvement

Treatment

Bortezomib based induction <- a myeloma directed therapy
Melphalan
Haematopoietic cell transplantation.

Prognosis

This disorder has a poor long-term prognosis, with cardiac or hepatic failure, and infection being the major causes of death
Earlier detection confers better outcome.

AA amyloidosis

The most common organ affected by AA amyloid is the kidney (approximately 80 percent of patients -> causes nephrotic syndrome.

Seen in Chronic inflammatory disorders include rheumatoid arthritis, inflammatory bowel disease and untreated familial Mediterranean fever.

AA amyloidosis may complicate chronic diseases in which there is ongoing or recurring inflammation, such as rheumatoid arthritis (RA), spondyloarthritis, or inflammatory bowel disease; chronic infections.

Symptoms

SImilar to AL (but cardiomyopathy is rare)
GI involvement: similar to AA amyloidosis

Treatment

In untreated patients, AA (secondary) amyloidosis carries a significant risk of mortality due to end-stage kidney disease, infection, heart failure, bowel perforation, or gastrointestinal bleeding.
Successful treatment of the underlying inflammatory process improves kidney function.
Treatment of the underlying condition can control but not cure amyloidosis.
For transthyretin type amyloidosis, liver transplant is definitive therapy as the liver is where transthyretin is made.

Spondyloarthritis (SpA)

Spondylos = greek for vertebrae

common features

• chronic low back pain
• positivity for HLA B27 antigen (present in 90% of those with AS)
  • (However, there is high background positivity of approx 8% so HLA isn't usually used in diagnosis. )
• radiographic changes in the sacroiliac joints in patients with axial SpA
• and asymmetric (oligo)arthritis, heel enthesitis and dactylitis in patients with peripheral SpA
• uveitis, inflammatory bowel disease, psoriasis, and increased levels of acute phase reactants

Uveitis
The presence of leukocytes in the anterior chamber of the eye is characteristic of anterior uveitis.
The presence of leukocytes in the vitreous humor - intermediate uveitis
Evidence of active chorioretinal inflammation -> posterior uveitis

• Rheumatoid factors negative. (<- Seronegative arthropathies)

Characteristic radiographic features

Sacroiliac joint:

• sclerosis,
• joint space widening, or erosion (fusion in late stages)

Syndesmophytes and changes of spondylitis in the spine, which are most often detected in more longstanding disease.

A syndesmophyte is a bony growth originating inside a ligament, commonly seen in the ligaments of the spine, specifically the ligaments in the intervertebral joints leading to fusion of vertebrae.

Inflammatory osteoproliferative lesions in the spine are called syndesmophytes (marginal and non-marginal), and degenerative osteoproliferative lesions are called osteophytes. Syndesmophytes are more vertically oriented than osteophytes.

Subtypes of SpA

[!TIP] Mnemonic: RePsAnkIb

• Reactive
• Psoriatic
• Anky spondylos
• IBD associated

• Ankylosing spondylitis
• Psoriatic arthritis
• Reactive arthritis
• IBD related arthritis
• And some other types
  • nonradiographic axial SpA (nr-axSpA), peripheral SpA,
• Also, always think about [[2023-SEMPaper]] <- whipple's disease.

[!INFO] Mnemonic: PAIR
Mnemonic for spondyloarthritis : PAIR ->

Ankylosing spondylitis

#2022GM Q25
#2022GM Q27

Ankylosing = stiffness or fixation of a joint by disease

Affects teens to early 30s, male >> female (5:1).
Pathology: lymphocyte and plasma cell infiltration of the attachments of ligaments. (enthesitis)

Some terminology: not super important

Pathogenesis of Ankylosing spondylitis

SourceGreat article!

HLA-B27

[!INFO] Key points

• It's largely a genetic disease - Patient's children have increased risk of getting it
• Pathogenesis consists of inflammation, bone erosion and syndesmophyte formation.
• Bone erosion and syndesmophyte formation are probably not linked to inflammation
• TNF-blockage suppresses symptoms but doesn't arrest bone changes.
  
  

Clinical features of AS

[!TIP] mnemonic:
Extra-articular complications all begin with A:

• Apical fibrosis
• Anterior uveitis
• Aortic regurgitation
• Achilles tendonitis
• AV node block
• Amyloidosis
  -passMedicine

• Intermittent episodes of sacroiliac joint inflammation
  • Chronic back pain which is reduced by exercise.
• Uveitis and costochondritis suggest back pain of rheumatic origin (i.e AS)
• Peripheral Joint involvement is asymmetrical and involves the large joints.
  • (eg Hip)ankles, hips, knees, shoulders, and the sternoclavicular joints
• Axial joints
  • Formation of syndesmophytes can lead to fusion of vertebrae. (Shobers test detects a stiff spine in early stages)
  • Advanced cases: fusion of the sacroiliac joints, and bamboo spine. (Gadolinum MRI is more sensitive than Xray at detecting early changes).
• Dactylitis - sausage shaped fingers and toes
• Extra-articular manifestations
  • Uveitis - can present as painful eye with photophobia and blurred vision -> emergency!
  • Aortitis

Diagnosis

"Plain x-ray of the sacroiliac joints is the most useful investigation in establishing the diagnosis."

• sacroiliitis is usually the first manifestation 5 and is symmetrical and bilateral
  • the sacroiliac joints first widen before they narrow
  • subchondral erosions, sclerosis, and proliferation on the iliac side of the SI joints
  • at end-stage, the SI joint may be seen as a thin line or not visible

The sacroiliac joint is actually a synovial joint with hyaline on the sacral surface and fibrous cartilage on the iliac surface Source.

Management of Anky Spondi

• Prevention of syndesmophyte formation -> early diagnosis and initiation of exercise regimen.
• NSAIDS for pain relief to enable exercise during exacerbations.
• MTX -> good for peripheral arthritis but will not work for spinal disease. Only exercise👆
• TNF-α blockers - etanercept and adalimumab provide HUGE symptomatic relief. They reduced morbidity
• Children of affected person have a 30% change of developing anky Spondi.
• Overall prognosis is good with exercise and pain relief, allowing 80% of patients to remain employed.

Aplastic anaemia

#2022GM Q30

Congenital

• fanconi anaemia

• dyskeratosis congenita
• Familiar aplastic anaemia
• Cartillage hair hypoplasia
• Diamond-blackfan anaemia

Acquired

• infection - EBV, hepatitis, parvovirus, mycobacteria
• Ionizing radiation
• Benzene, pesticides
• GVHD
• Pregnancy
• anorexia, severe nutritional deficiencies
• PNH

Hepatosplenomegaly and lymphadenopathy are rare.

Bone changes seen in various diseases

Bradykinin

[!TIP] Mnemonic : BPH - bradykinin, prostaglandin and histamine act together.

• Bradykinin is peptide with a half life of 17 seconds!.
  • "Bradykinin makes blood vessels look like leaky barrel" - B for barrel and bradykinin
  • 
• potent vasodilator. -> accumulation causes angiooedema and possibly the dry cough of ACEi therapy.
• Broken down by BOTH
  • ACE and
  • neprilysin.
• See [[ARNIMechanism.png]]
  
• C1 esterase is a complement activation inhibitor. (Also called C1-INH for inhibitor)
• Defieciency of C1 esterase causes unchecked activation of C1, C2 and C4. (i.e classical pathway)
• This causes activation of kallikrein which causes increased production of bradykinin --> angiooedema.
• Low C2 and C4 levels are seen in hereditary angioedema.
• Serum C4 is the most reliable and widely used screening tool
• Treatment: plasma derived C1 inhibitor. Fresh frozen plasma (FFP) if this is not available

| | |

[!INFO] Up to 1 year post op for valve replacement, staph epidermidis >> staph aureaus.
[[aetiologicAgentsInfectiveEndocarditis.png]]

HACEK denotes Haemophilus species, Actinobacillus actinomycetemcomitans, Cardiobacterium hominis, Eikenella corrodens and Kingella kingae.

- They are also some of the oldest antiepileptics. Newer drugs have better pharmacokinetics. 
- The narrow spectrum AEDs mostly work for specific types of seizures (such as focal, absence, **or** myoclonic seizures). 
- Broad spectrum AEDs additionally have some effectiveness for a *wide variety of seizures* (focal **plus** absence myoclonic seizures).

Source
- Mnemonic: cOllECtIvE (COLLECTIVE IS SIMILAR TO 'BROADLY') (LeCo-VoLT)

• Valproate, lamotrigine and levetiracetam are newer antiepileptic drugs so they have broader spectrum than the older ones. These 3 are active against both primary and secondary generalized epilepsy. (secondary generalized means "Focal to bilateral tonic-clonic seizure")
• Mnemonic: VLL
• Valproate is good for almost everything, including absence, myotonic, myoclonic, partial, secondary generalized. However, valproate should be avoided in females of child bearing age.
• Spectrum of lamotrigine is similar but it can worsen myoclonic seizures.
• Passmedicine: lamotrigine and levetiracetam are used for focal seizures.
• Levetiracetam: Drug of choice for partial and / or secondary generalized seizures. Non sedating.

Generalized Anxiety disorder

Source

• DSM-5 definition: "excessive worry that occurs on most days for at least six months and causes significant distress or impairment" + 3 or more of the following + and the disturbance cannot be explained by another mental disorder (i.e to exclude anxiety due to obsession, social phobia etc)
  1. Restlessness
  2. Easily fatigued
  3. Difficulty concentrating or mind going blank
  4. Irritability
  5. Muscle tension
  6. Poor sleep

Treatment: See [[#Treatment for GAD and panic disorder]] below.

• Antidepressants, SSRIs and SNRIs in particular, are considered first-line therapies for GAD and PD because they are effective and generally well tolerated.Source

Panic disorder

Source
PD is defined by the DSM-5 as recurrent panic attacks that include characteristic symptoms and lack an obvious trigger followed by concern about another attack lasting for at least 1 month.
Panic attacks that are nocturnal or lack fear require a more extensive workup.
Commonest symptoms is palpitations.
"panic attack": an intense surge of fear or discomfort which peaks within minutes which are associated with many physical symptoms including chest pain.

Treatment for GAD and panic disorder

Source

• Cognitive behavioural therapy.
• Pharmacotherapy:
  • SNRIs and SSRIs are first line.
  • GAD: Should be taken for 12 months to prevent relapse.
  • PD: Treatment for 2 to 6 months.
  • Benzodiazepines relieve symptoms in the short term but are not recommended for long term use due to rebound symptoms and dependence.

If > 8 hours since ingection, NAC is given rather than methionine.

[!INFO] Paracetamol
1,4,8,16
Gastric lavage 1 hour.
Activated charcoal 4 hours. Levels also at 4 hours.
Before 8 hour, methionine can be given and is as effective as NAC.
After 8 hours, give NAC.
Liver damange unlikely if NAC started within 8 hours.

Criteria for liver transplantation

King's College Hospital criteria for liver transplantation (paracetamol liver failure)

• Arterial pH < 7.3, 24 hours after ingestion

• or all of the following:

  • prothrombin time > 100 seconds
  • creatinine > 300 µmol/l
  • grade III or IV encephalopathy
    ECG: widened QRS, AV block, ventricular arrhythmias

• respiratory alkalosis – hyperventilation (in early stages with high salicylate levels)

• metabolic acidosis – lactate
  hypokalemia
  Management

• supportive

• alkaline diuresis was used earlier

almost identical to cinchonism (quinine toxicity).

• visual impairment favours a diagnosis of quinine toxicity
• In terms of management however, whereas aspirin can be cleared from overdose victims by haemofiltration, quinine cannot be extracted easily by extracorporeal methods. Central nervous symptoms such as tinnitus, deafness and visual defects which may occur with aspirin are usually transient whereas quinine leaves permanent neural damage, if the patient survives.

Organophosphate and carbamate poisoning

• They are both acetylcholinesterase inhibitors causing nicotinic and muscarinic symptoms.
• Nicotinic symptoms - pralidoxime. (for OP only)
• Muscarinic symptoms - atropine.

Carbamate toxicity

#2022SBR-MAY/Q16
#2016GM-APR/Q05

• Used as insecticides.
• Similar mechanism of action to organophosphate.
• However, carbamates inhibit acetylcholinesterase reversibly, while organophosphates inhibit acetylcholinesterase irreversibly.
• Therefore, duration of toxicity is typically < 24 hours.
• Pralidoxime is of no value in treatment.

Organophosphate poisoning

SLUDGE/BBB – Salivation, Lacrimation, Urination, Defecation, Gastric Emesis, Bronchorrhea, Bronchospasm, Bradycardia, and Miosis

 - Mainly Proximal Muscle weakness: characteristic neurological findings including neck flexion weakness, decreased deep tendon reflexes, cranial nerve abnormalities, proximal muscle weakness, and respiratory insufficiency
 - Complete resolution occurs in 2-3 weeks if the patient receives ventilatory support
 - Intermediate syndrome is rarer with carbamate poisoning Source but it can occur.

Several weeks after exposure
Characterized by distal weakness and sensory loss first in the lower limbs; may progress proximally and affect upper extremities.
This occurs due to inhibition of neuropathy target esterase (NTE) by organophosphates.
Carbamates are generally though to not cause neuropathy because the acetylcholinesterase bone is reversible- but some cases have been reported. Source

Non alcoholic fatty liver disease (NASH)/(NALFD)

Hypersensitivity pneumonitis (HP)

Source

• Caused by sensitization and reexposure to allergens, often associated with occupations.
• Clinical features are cough, dyspnoea, fatigue
• Most commonly associated with farming, birds and water contamination.
• eg: farmers lung, Bird fancier's lung, cheese washer's lung, hot tub lung, wine grower's lung.
• HP is caused by a Type IV hypersensitivity reaction.
• Repeated exposure to antigen in genetically susceptible people leads to acute neutrophilic and mononuclear alveolitis, followed by interstitial lymphocytic infiltration and granulomatous reaction.
• Contrast with
  • pneumoconioses where the damage is caused by inflammation resulting from particle deposition in the lung.
  • Organic dust toxic syndrome / silo fillers lung - where toxins in the inhaled particles cause lung damage.
  • Occupational asthma - but OA has airflow obstruction, airway eosinophilia, and different triggering antigens.

Symptoms

Investigations
CXR - Non specific.
HRCT - profuse, poorly defined centrilobular micronodules is the most characteristic findings. Fibrosis in Chronic HP.
BAL - Lymphocytosis with CD8+ predominance. (lymphocytosis with CD4+ predominant is seen in sarcoidosis)

Treatment:

• Acute: Steroids + antigen avoidance-> Completely reversible.
• Chronic: Longer term steroids; fibrosis is irreversible.

Side effects of chemotherapy drugs